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Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26]In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[148] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[149]

Athletes might adopt gene therapy technologies to improve their performance.[150] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[151]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[152][153][154] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[155][156] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[157]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[158]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[159] and such concerns have continued as technology progressed.[160][161] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[148][162] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[163][164] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[165]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[166]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[167]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[168] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[169] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[168]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[170][171]

Gene therapy is the basis for the plotline of the film I Am Legend[172] and the TV show Will Gene Therapy Change the Human Race?.[173] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[174]

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Gene therapy – Wikipedia

Gene Therapy Retrovirus Vectors Explained

A retrovirus is any virus belonging to the viral family Retroviridae. All The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be considered part of the genetic material of the host cell. Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus. Group-specific antigen (gag) codes for core and structural proteins of the virus, polymerase (pol) codes for reverse transcriptase, protease and integrase, and envelope (env) codes for the retroviral coat proteins (see figure 1). Figure 1. Genome organisation of retroviruses.

The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase (see figure 2).

Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, we can say that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

Retroviral vectors are created by removal op the retroviral gag, pol, and env genes. These are replaced by the therapeutic gene. In order to produce vector particles a packaging cell is essential. Packaging cell lines provide all the viral proteins required for capsid production and the virion maturation of the vector. These packaging cell lines have been made so that they contain the gag, pol and env genes. Early packaging cell lines contained replication competent retroviral genomes and a single recombination event between this genome and the retroviral DNA vector could result in the production of a wild type virus. Following insertion of the desired gene into in the retroviral DNA vector, and maintainance of the proper packaging cell line, it is now a simple matter to prepare retroviral vectors (see figure 3).

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French X-linked SCID (X-SCID) gene therapy trial. Ten X-SCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan.

As a reaction to the adverse events in the French X-SCID gene therapy trial, the Recombinant DNA Advisory Committee (RAC) sent a letter to Principal Investigators Conveying RAC Recommendations in 2003. In addition, the RAC published conclusions and recommendations of the RAC Gene Transfer Safety Symposium in 2005. A joint working party of the Gene Therapy Advisory Committee and the Committee on Safety of Medicines (CSM) in the UK lead to the publication of an updated recommendations of the GTAC/CSM working party on retroviruses in 2005.

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Gene Therapy Retrovirus Vectors Explained

Gene Therapy Net – News, Conferences, Vectors, Literature …

Posted on: 22 March 2018, source: GizmodoOn Tuesday, a 13-year-old boy from New Jersey was at the center of medical history as he became the first person in the US to receive an FDA-approved gene therapy for an inherited disease. The event marks the beginning of a new era of medicine, one in which devastating genetic conditions that we are born with can be simply edited out of our DNA with the help of modern biomedical technologies. The therapy, Luxturna, from Spark Therepeutics, was approved by the FDA in December to treat a rare, inherited form of blindness. Its price tag, set at $850,000or $425,000 per eyemade it the most expensive drug in the US and sparked mass sticker-shock. But the therapy, which in high-profile clinical trials has allowed patients to see the stars for the first times, also offered the almost miraculous possibility of giving sight to the blind.

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Gene Therapy Net – News, Conferences, Vectors, Literature …

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26]In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[148] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[149]

Athletes might adopt gene therapy technologies to improve their performance.[150] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[151]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[152][153][154] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[155][156] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[157]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[158]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[159] and such concerns have continued as technology progressed.[160][161] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[148][162] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[163][164] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[165]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[166]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[167]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[168] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[169] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[168]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[170][171]

Gene therapy is the basis for the plotline of the film I Am Legend[172] and the TV show Will Gene Therapy Change the Human Race?.[173] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[174]

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Gene therapy – Wikipedia

Gene Therapy Net – Official Site

Posted on: 22 March 2018, source: GizmodoOn Tuesday, a 13-year-old boy from New Jersey was at the center of medical history as he became the first person in the US to receive an FDA-approved gene therapy for an inherited disease. The event marks the beginning of a new era of medicine, one in which devastating genetic conditions that we are born with can be simply edited out of our DNA with the help of modern biomedical technologies. The therapy, Luxturna, from Spark Therepeutics, was approved by the FDA in December to treat a rare, inherited form of blindness. Its price tag, set at $850,000or $425,000 per eyemade it the most expensive drug in the US and sparked mass sticker-shock. But the therapy, which in high-profile clinical trials has allowed patients to see the stars for the first times, also offered the almost miraculous possibility of giving sight to the blind.

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Gene Therapy Net – Official Site

Gene Therapy Retrovirus Vectors Explained

A retrovirus is any virus belonging to the viral family Retroviridae. All The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be considered part of the genetic material of the host cell. Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus. Group-specific antigen (gag) codes for core and structural proteins of the virus, polymerase (pol) codes for reverse transcriptase, protease and integrase, and envelope (env) codes for the retroviral coat proteins (see figure 1). Figure 1. Genome organisation of retroviruses.

The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase (see figure 2).

Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, we can say that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

Retroviral vectors are created by removal op the retroviral gag, pol, and env genes. These are replaced by the therapeutic gene. In order to produce vector particles a packaging cell is essential. Packaging cell lines provide all the viral proteins required for capsid production and the virion maturation of the vector. These packaging cell lines have been made so that they contain the gag, pol and env genes. Early packaging cell lines contained replication competent retroviral genomes and a single recombination event between this genome and the retroviral DNA vector could result in the production of a wild type virus. Following insertion of the desired gene into in the retroviral DNA vector, and maintainance of the proper packaging cell line, it is now a simple matter to prepare retroviral vectors (see figure 3).

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French X-linked SCID (X-SCID) gene therapy trial. Ten X-SCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan.

As a reaction to the adverse events in the French X-SCID gene therapy trial, the Recombinant DNA Advisory Committee (RAC) sent a letter to Principal Investigators Conveying RAC Recommendations in 2003. In addition, the RAC published conclusions and recommendations of the RAC Gene Transfer Safety Symposium in 2005. A joint working party of the Gene Therapy Advisory Committee and the Committee on Safety of Medicines (CSM) in the UK lead to the publication of an updated recommendations of the GTAC/CSM working party on retroviruses in 2005.

Continued here:

Gene Therapy Retrovirus Vectors Explained

Gene Therapy Net – News, Conferences, Vectors, Literature …

Posted on: 22 March 2018, source: GizmodoOn Tuesday, a 13-year-old boy from New Jersey was at the center of medical history as he became the first person in the US to receive an FDA-approved gene therapy for an inherited disease. The event marks the beginning of a new era of medicine, one in which devastating genetic conditions that we are born with can be simply edited out of our DNA with the help of modern biomedical technologies. The therapy, Luxturna, from Spark Therepeutics, was approved by the FDA in December to treat a rare, inherited form of blindness. Its price tag, set at $850,000or $425,000 per eyemade it the most expensive drug in the US and sparked mass sticker-shock. But the therapy, which in high-profile clinical trials has allowed patients to see the stars for the first times, also offered the almost miraculous possibility of giving sight to the blind.

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Gene Therapy Net – News, Conferences, Vectors, Literature …

Gene Therapy | Pfizer: One of the world’s premier …

Gene therapy is a technology aimed at correcting or fixing a gene that may be defective. This exciting and potentially transformative area of research is focused on the development of potential treatments for monogenic diseases, or diseases that are caused by a defect in one gene.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

Viral vectors can be developed using adeno-associated virus (AAV), a naturally occurring virus which has been adapted for gene therapy use. Its ability to deliver genetic material to a wide range of tissues makes AAV vectors useful for transferring therapeutic genes into target cells. Gene therapy research holds tremendous promise in leading to the possible development of highly-specialized, potentially one-time delivery treatments for patients suffering from rare, monogenic diseases.

Pfizer aims to build an industry-leading gene therapy platform with a strategy focused on establishing a transformational portfolio through in-house capabilities, and enhancing those capabilities through strategic collaborations, as well as potential licensing and M&A activities.

We’re working to access the most effective vector designs available to build a robust clinical stage portfolio, and employing a scalable manufacturing approach, proprietary cell lines and sophisticated analytics to support clinical development.

In addition, we’re collaborating with some of the foremost experts in this field, through collaborations with Spark Therapeutics, Inc., on a potentially transformative gene therapy treatment for hemophilia B, which received Breakthrough Therapy designation from the US Food and Drug Administration, and 4D Molecular Therapeutics to discover and develop targeted next-generation AAV vectors for cardiac disease.

Gene therapy holds the promise of bringing true disease modification for patients suffering from devastating diseases, a promise were working to seeing become a reality in the years to come.

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Gene Therapy | Pfizer: One of the world’s premier …

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147] CRISPR gene editing technology has also been used on mice to treat deafness due to the DFNA36 mutation, which also affects humans.[148]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[149] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[150]

Athletes might adopt gene therapy technologies to improve their performance.[151] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[152]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[153][154][155] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[156][157] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[158]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[159]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[160] and such concerns have continued as technology progressed.[161][162] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[149][163] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[164][165] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[166]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[167]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[168]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[169] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[170] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[169]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[171][172]

Gene therapy is the basis for the plotline of the film I Am Legend[173] and the TV show Will Gene Therapy Change the Human Race?.[174] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[175]

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Gene therapy – Wikipedia

Gene Therapy Net – News, Conferences, Vectors, Literature …

Posted on: 22 March 2018, source: GizmodoOn Tuesday, a 13-year-old boy from New Jersey was at the center of medical history as he became the first person in the US to receive an FDA-approved gene therapy for an inherited disease. The event marks the beginning of a new era of medicine, one in which devastating genetic conditions that we are born with can be simply edited out of our DNA with the help of modern biomedical technologies. The therapy, Luxturna, from Spark Therepeutics, was approved by the FDA in December to treat a rare, inherited form of blindness. Its price tag, set at $850,000or $425,000 per eyemade it the most expensive drug in the US and sparked mass sticker-shock. But the therapy, which in high-profile clinical trials has allowed patients to see the stars for the first times, also offered the almost miraculous possibility of giving sight to the blind.

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Gene Therapy Net – News, Conferences, Vectors, Literature …

Gene Therapy Technology Explanied

Virtually all cells in the human body contain genes, making them potential targets for gene therapy. However, these cells can be divided into two major categories: somatic cells (most cells of the body) or cells of the germline (eggs or sperm). In theory it is possible to transform either somatic cells or germ cells.

Gene therapy using germ line cells results in permanent changes that are passed down to subsequent generations. If done early in embryologic development, such as during preimplantation diagnosis and in vitro fertilization, the gene transfer could also occur in all cells of the developing embryo. The appeal of germ line gene therapy is its potential for offering a permanent therapeutic effect for all who inherit the target gene. Successful germ line therapies introduce the possibility of eliminating some diseases from a particular family, and ultimately from the population, forever. However, this also raises controversy. Some people view this type of therapy as unnatural, and liken it to “playing God.” Others have concerns about the technical aspects. They worry that the genetic change propagated by germ line gene therapy may actually be deleterious and harmful, with the potential for unforeseen negative effects on future generations.

Somatic cells are nonreproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. However, this type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual’s life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic. Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially correcting or treating a life-threatening disorder that may significantly impair a baby’s health or development if not treated before birth.

In summary, the distinction is that the results of any somatic gene therapy are restricted to the actual patient and are not passed on to his or her children. All gene therapy to date on humans has been directed at somatic cells, whereas germline engineering in humans remains controversial and prohibited in for instance the European Union.

Somatic gene therapy can be broadly split into two categories:

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Gene Therapy Technology Explanied

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body’s cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body’s form and function, from making you grow taller to regulating your body systems. Genes that don’t work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body’s ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can’t easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren’t the only vectors that can be used to carry altered genes into your body’s cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 29, 2017

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Gene therapy – Mayo Clinic

Libertarianism – Wikipedia

“Libertarians” redirects here. For political parties that may go by this name, see Libertarian Party.

Libertarianism (from Latin: libertas, meaning “freedom”) is a collection of political philosophies and movements that uphold liberty as a core principle.[1] Libertarians seek to maximize political freedom and autonomy, emphasizing freedom of choice, voluntary association, and individual judgment.[2][3][4] Libertarians share a skepticism of authority and state power, but they diverge on the scope of their opposition to existing political and economic systems. Various schools of libertarian thought offer a range of views regarding the legitimate functions of state and private power, often calling for the restriction or dissolution of coercive social institutions.[5]

Left-libertarian ideologies seek to abolish capitalism and private ownership of the means of production, or else to restrict their purview or effects, in favor of common or cooperative ownership and management, viewing private property as a barrier to freedom and liberty.[6][7][8][9] In contrast, modern right-libertarian ideologies, such as minarchism and anarcho-capitalism, instead advocate laissez-faire capitalism and strong private property rights,[10] such as in land, infrastructure, and natural resources.

The first recorded use of the term “libertarian” was in 1789, when William Belsham wrote about libertarianism in the context of metaphysics.[11]

“Libertarian” came to mean an advocate or defender of liberty, especially in the political and social spheres, as early as 1796, when the London Packet printed on 12 February: “Lately marched out of the Prison at Bristol, 450 of the French Libertarians”.[12] The word was again used in a political sense in 1802 in a short piece critiquing a poem by “the author of Gebir” and has since been used with this meaning.[13][14][15]

The use of the word “libertarian” to describe a new set of political positions has been traced to the French cognate, libertaire, coined in a letter French libertarian communist Joseph Djacque wrote to mutualist Pierre-Joseph Proudhon in 1857.[16][17][18] Djacque also used the term for his anarchist publication Le Libertaire: Journal du Mouvement Social, which was printed from 9 June 1858 to 4 February 1861 in New York City.[19][20] In the mid-1890s, Sbastien Faure began publishing a new Le Libertaire while France’s Third Republic enacted the lois sclrates (“villainous laws”), which banned anarchist publications in France. Libertarianism has frequently been used as a synonym for anarchism since this time.[21][22][23]

The term “libertarianism” was first used in the United States as a synonym for classic liberalism in May 1955 by writer Dean Russell, a colleague of Leonard Read and a classic liberal himself. He justified the choice of the word as follows: “Many of us call ourselves ‘liberals.’ And it is true that the word ‘liberal’ once described persons who respected the individual and feared the use of mass compulsions. But the leftists have now corrupted that once-proud term to identify themselves and their program of more government ownership of property and more controls over persons. As a result, those of us who believe in freedom must explain that when we call ourselves liberals, we mean liberals in the uncorrupted classical sense. At best, this is awkward and subject to misunderstanding. Here is a suggestion: Let those of us who love liberty trade-mark and reserve for our own use the good and honorable word ‘libertarian'”.[24]

Subsequently, a growing number of Americans with classical liberal beliefs in the United States began to describe themselves as “libertarian”. The person most responsible for popularizing the term “libertarian” was Murray Rothbard,[25] who started publishing libertarian works in the 1960s.

Libertarianism in the United States has been described as conservative on economic issues and liberal on personal freedom[26] (for common meanings of conservative and liberal in the United States) and it is also often associated with a foreign policy of non-interventionism.[27][28]

Although the word “libertarian” has been used to refer to socialists internationally, its meaning in the United States has deviated from its political origins.[29][30]

There is contention about whether left and right libertarianism “represent distinct ideologies as opposed to variations on a theme”.[31] All libertarians begin with a conception of personal autonomy from which they argue in favor of civil liberties and a reduction or elimination of the state.

Left-libertarianism encompasses those libertarian beliefs that claim the Earth’s natural resources belong to everyone in an egalitarian manner, either unowned or owned collectively. Contemporary left-libertarians such as Hillel Steiner, Peter Vallentyne, Philippe Van Parijs, Michael Otsuka and David Ellerman believe the appropriation of land must leave “enough and as good” for others or be taxed by society to compensate for the exclusionary effects of private property. Libertarian socialists (social and individualist anarchists, libertarian Marxists, council communists, Luxemburgists and DeLeonists) promote usufruct and socialist economic theories, including communism, collectivism, syndicalism and mutualism. They criticize the state for being the defender of private property and believe capitalism entails wage slavery.

Right-libertarianism[32] developed in the United States in the mid-20th century and is the most popular conception of libertarianism in that region.[33] It is commonly referred to as a continuation or radicalization of classical liberalism.[34][35] Right-libertarians, while often sharing left-libertarians’ advocacy for social freedom, also value the social institutions that enforce conditions of capitalism, while rejecting institutions that function in opposition to these on the grounds that such interventions represent unnecessary coercion of individuals and abrogation of their economic freedom.[36] Anarcho-capitalists[37][38] seek complete elimination of the state in favor of privately funded security services while minarchists defend “night-watchman states”, which maintain only those functions of government necessary to maintain conditions of capitalism and personal security.

Anarchism envisages freedom as a form of autonomy,[39] which Paul Goodman describes as “the ability to initiate a task and do it one’s own way, without orders from authorities who do not know the actual problem and the available means”.[40] All anarchists oppose political and legal authority, but collectivist strains also oppose the economic authority of private property.[41] These social anarchists emphasize mutual aid, whereas individualist anarchists extoll individual sovereignty.[42]

Some right-libertarians consider the non-aggression principle (NAP) to be a core part of their beliefs.[43][44]

Libertarians have been advocates and activists of civil liberties, including free love and free thought.[45][46] Advocates of free love viewed sexual freedom as a clear, direct expression of individual sovereignty and they particularly stressed women’s rights as most sexual laws discriminated against women: for example, marriage laws and anti-birth control measures.[47]

Free love appeared alongside anarcha-feminism and advocacy of LGBT rights. Anarcha-feminism developed as a synthesis of radical feminism and anarchism and views patriarchy as a fundamental manifestation of compulsory government. It was inspired by the late-19th-century writings of early feminist anarchists such as Lucy Parsons, Emma Goldman, Voltairine de Cleyre and Virginia Bolten. Anarcha-feminists, like other radical feminists, criticise and advocate the abolition of traditional conceptions of family, education and gender roles. Free Society (18951897 as The Firebrand, 18971904 as Free Society) was an anarchist newspaper in the United States that staunchly advocated free love and women’s rights, while criticizing “comstockery”, the censorship of sexual information.[48] In recent times, anarchism has also voiced opinions and taken action around certain sex-related subjects such as pornography,[49] BDSM[50] and the sex industry.[50]

Free thought is a philosophical viewpoint that holds opinions should be formed on the basis of science, logic and reason in contrast with authority, tradition or other dogmas.[51][52] In the United States, free thought was an anti-Christian, anti-clerical movement whose purpose was to make the individual politically and spiritually free to decide on religious matters. A number of contributors to Liberty were prominent figures in both free thought and anarchism. In 1901, Catalan anarchist and free-thinker Francesc Ferrer i Gurdia established “modern” or progressive schools in Barcelona in defiance of an educational system controlled by the Catholic Church.[53] Fiercely anti-clerical, Ferrer believed in “freedom in education”, i.e. education free from the authority of the church and state.[54] The schools’ stated goal was to “educate the working class in a rational, secular and non-coercive setting”. Later in the 20th century, Austrian Freudo-Marxist Wilhelm Reich became a consistent propagandist for sexual freedom going as far as opening free sex-counselling clinics in Vienna for working-class patients[55] as well as coining the phrase “sexual revolution” in one of his books from the 1940s.[56] During the early 1970s, the English anarchist and pacifist Alex Comfort achieved international celebrity for writing the sex manuals The Joy of Sex and More Joy of Sex.

Most left-libertarians are anarchists and believe the state inherently violates personal autonomy: “As Robert Paul Wolff has argued, since ‘the state is authority, the right to rule’, anarchism which rejects the State is the only political doctrine consistent with autonomy in which the individual alone is the judge of his moral constraints”.[41] Social anarchists believe the state defends private property, which they view as intrinsically harmful, while market-oriented left-libertarians argue that so-called free markets actually consist of economic privileges granted by the state. These latter libertarians advocate instead for freed markets, which are freed from these privileges.[57]

There is a debate amongst right-libertarians as to whether or not the state is legitimate: while anarcho-capitalists advocate its abolition, minarchists support minimal states, often referred to as night-watchman states. Libertarians take a skeptical view of government authority.[58][unreliable source?] Minarchists maintain that the state is necessary for the protection of individuals from aggression, theft, breach of contract and fraud. They believe the only legitimate governmental institutions are the military, police and courts, though some expand this list to include fire departments, prisons and the executive and legislative branches.[59] They justify the state on the grounds that it is the logical consequence of adhering to the non-aggression principle and argue that anarchism is immoral because it implies that the non-aggression principle is optional, that the enforcement of laws under anarchism is open to competition.[citation needed] Another common justification is that private defense agencies and court firms would tend to represent the interests of those who pay them enough.[60]

Anarcho-capitalists argue that the state violates the non-aggression principle (NAP) by its nature because governments use force against those who have not stolen or vandalized private property, assaulted anyone or committed fraud.[61][62] Linda & Morris Tannehill argue that no coercive monopoly of force can arise on a truly free market and that a government’s citizenry can not desert them in favor of a competent protection and defense agency.[63]

Left-libertarians believe that neither claiming nor mixing one’s labor with natural resources is enough to generate full private property rights[64][65] and maintain that natural resources ought to be held in an egalitarian manner, either unowned or owned collectively.[66]

Right-libertarians maintain that unowned natural resources “may be appropriated by the first person who discovers them, mixes his labor with them, or merely claims themwithout the consent of others, and with little or no payment to them”. They believe that natural resources are originally unowned and therefore private parties may appropriate them at will without the consent of, or owing to, others.[67]

Left-libertarians (social and individualist anarchists, libertarian Marxists and left-wing market anarchists) argue in favor of socialist theories such as communism, syndicalism and mutualism (anarchist economics). Daniel Gurin writes that “anarchism is really a synonym for socialism. The anarchist is primarily a socialist whose aim is to abolish the exploitation of man by man. Anarchism is only one of the streams of socialist thought, that stream whose main components are concern for liberty and haste to abolish the State”.[68]

Right-libertarians are economic liberals of either the Austrian School or Chicago school and support laissez-faire capitalism.[69]

Wage labour has long been compared by socialists and anarcho-syndicalists to slavery.[70][71][72][73] As a result, the term “wage slavery” is often utilised as a pejorative for wage labor.[74] Advocates of slavery looked upon the “comparative evils of Slave Society and of Free Society, of slavery to human Masters and slavery to Capital”[75] and proceeded to argue that wage slavery was actually worse than chattel slavery.[76] Slavery apologists like George Fitzhugh contended that workers only accepted wage labour with the passage of time, as they became “familiarized and inattentive to the infected social atmosphere they continually inhale[d]”.[75]

According to Noam Chomsky, analysis of the psychological implications of wage slavery goes back to the Enlightenment era. In his 1791 book On the Limits of State Action, classical liberal thinker Wilhelm von Humboldt explained how “whatever does not spring from a man’s free choice, or is only the result of instruction and guidance, does not enter into his very nature; he does not perform it with truly human energies, but merely with mechanical exactness” and so when the labourer works under external control “we may admire what he does, but we despise what he is”.[77] For Marxists, labour-as-commodity, which is how they regard wage labour,[78] provides an absolutely fundamental point of attack against capitalism.[79] “It can be persuasively argued”, noted philosopher John Nelson, “that the conception of the worker’s labour as a commodity confirms Marx’s stigmatization of the wage system of private capitalism as ‘wage-slavery;’ that is, as an instrument of the capitalist’s for reducing the worker’s condition to that of a slave, if not below it”.[80] That this objection is fundamental follows immediately from Marx’s conclusion that wage labour is the very foundation of capitalism: “Without a class dependent on wages, the moment individuals confront each other as free persons, there can be no production of surplus value; without the production of surplus-value there can be no capitalist production, and hence no capital and no capitalist!”.[81]

Left-libertarianism (or left-wing libertarianism) names several related, but distinct approaches to political and social theory which stresses both individual freedom and social equality. In its classical usage, left-libertarianism is a synonym for anti-authoritarian varieties of left-wing politics, i.e. libertarian socialism, which includes anarchism and libertarian Marxism, among others.[82][83] Left-libertarianism can also refer to political positions associated with academic philosophers Hillel Steiner, Philippe Van Parijs and Peter Vallentyne that combine self-ownership with an egalitarian approach to natural resouces.[84]

While maintaining full respect for personal property, left-libertarians are skeptical of or fully against private property, arguing that neither claiming nor mixing one’s labor with natural resources is enough to generate full private property rights[85][86] and maintain that natural resources (land, oil, gold and vegetation) should be held in an egalitarian manner, either unowned or owned collectively. Those left-libertarians who support private property do so under the condition that recompense is offered to the local community.[86] Many left-libertarian schools of thought are communist, advocating the eventual replacement of money with labor vouchers or decentralized planning.

On the other hand, left-wing market anarchism, which includes Pierre-Joseph Proudhon’s mutualism and Samuel Edward Konkin III’s agorism, appeals to left-wing concerns such as egalitarianism, gender and sexuality, class, immigration and environmentalism within the paradigm of a socialist free market.[82]

Right-libertarianism (or right-wing libertarianism) refers to libertarian political philosophies that advocate negative rights, natural law and a major reversal of the modern welfare state.[87] Right-libertarians strongly support private property rights and defend market distribution of natural resources and private property.[88] This position is contrasted with that of some versions of left-libertarianism, which maintain that natural resources belong to everyone in an egalitarian manner, either unowned or owned collectively.[89] Right-libertarianism includes anarcho-capitalism and laissez-faire, minarchist liberalism.[note 1]

Elements of libertarianism can be traced as far back as the ancient Chinese philosopher Lao-Tzu and the higher-law concepts of the Greeks and the Israelites.[90][91] In 17th-century England, libertarian ideas began to take modern form in the writings of the Levellers and John Locke. In the middle of that century, opponents of royal power began to be called Whigs, or sometimes simply “opposition” or “country” (as opposed to Court) writers.[92]

During the 18th century, classical liberal ideas flourished in Europe and North America.[93][94] Libertarians of various schools were influenced by classical liberal ideas.[95] For libertarian philosopher Roderick T. Long, both libertarian socialists and libertarian capitalists “share a commonor at least an overlapping intellectual ancestry… both claim the seventeenth century English Levellers and the eighteenth century French encyclopedists among their ideological forebears; and (also)… usually share an admiration for Thomas Jefferson[96][97][98] and Thomas Paine”.[99]

John Locke greatly influenced both libertarianism and the modern world in his writings published before and after the English Revolution of 1688, especially A Letter Concerning Toleration (1667), Two Treatises of Government (1689) and An Essay Concerning Human Understanding (1690). In the text of 1689, he established the basis of liberal political theory: that people’s rights existed before government; that the purpose of government is to protect personal and property rights; that people may dissolve governments that do not do so; and that representative government is the best form to protect rights.[100] The United States Declaration of Independence was inspired by Locke in its statement: “[T]o secure these rights, Governments are instituted among Men, deriving their just powers from the consent of the governed. That whenever any Form of Government becomes destructive of these ends, it is the Right of the People to alter or to abolish it”.[101] Nevertheless scholar Ellen Meiksins Wood says that “there are doctrines of individualism that are opposed to Lockean individualism… and non-Lockean individualism may encompass socialism”.[102]

According to Murray Rothbard, the libertarian creed emerged from the classical liberal challenges to an “absolute central State and a king ruling by divine right on top of an older, restrictive web of feudal land monopolies and urban guild controls and restrictions”, the mercantilism of a bureaucratic warfaring state allied with privileged merchants. The object of classical liberals was individual liberty in the economy, in personal freedoms and civil liberty, separation of state and religion, and peace as an alternative to imperial aggrandizement. He cites Locke’s contemporaries, the Levellers, who held similar views. Also influential were the English “Cato’s Letters” during the early 1700s, reprinted eagerly by American colonists who already were free of European aristocracy and feudal land monopolies.[101]

In January of 1776, only two years after coming to America from England, Thomas Paine published his pamphlet Common Sense calling for independence for the colonies.[103] Paine promoted classical liberal ideas in clear, concise language that allowed the general public to understand the debates among the political elites.[104] Common Sense was immensely popular in disseminating these ideas,[105] selling hundreds of thousands of copies.[106] Paine later would write the Rights of Man and The Age of Reason and participate in the French Revolution.[103] Paine’s theory of property showed a “libertarian concern” with the redistribution of resources.[107]

In 1793, William Godwin wrote a libertarian philosophical treatise, Enquiry Concerning Political Justice and its Influence on Morals and Happiness, which criticized ideas of human rights and of society by contract based on vague promises. He took classical liberalism to its logical anarchic conclusion by rejecting all political institutions, law, government and apparatus of coercion as well as all political protest and insurrection. Instead of institutionalized justice, Godwin proposed that people influence one another to moral goodness through informal reasoned persuasion, including in the associations they joined as this would facilitate happiness.[108][109]

Modern anarchism sprang from the secular or religious thought of the Enlightenment, particularly Jean-Jacques Rousseau’s arguments for the moral centrality of freedom.[110]

As part of the political turmoil of the 1790s in the wake of the French Revolution, William Godwin developed the first expression of modern anarchist thought.[111][112] According to Peter Kropotkin, Godwin was “the first to formulate the political and economical conceptions of anarchism, even though he did not give that name to the ideas developed in his work”,[113] while Godwin attached his anarchist ideas to an early Edmund Burke.[114]

Godwin is generally regarded as the founder of the school of thought known as philosophical anarchism. He argued in Political Justice (1793)[112][115] that government has an inherently malevolent influence on society and that it perpetuates dependency and ignorance. He thought that the spread of the use of reason to the masses would eventually cause government to wither away as an unnecessary force. Although he did not accord the state with moral legitimacy, he was against the use of revolutionary tactics for removing the government from power. Rather, Godwin advocated for its replacement through a process of peaceful evolution.[112][116]

His aversion to the imposition of a rules-based society led him to denounce, as a manifestation of the people’s “mental enslavement”, the foundations of law, property rights and even the institution of marriage. Godwin considered the basic foundations of society as constraining the natural development of individuals to use their powers of reasoning to arrive at a mutually beneficial method of social organization. In each case, government and its institutions are shown to constrain the development of our capacity to live wholly in accordance with the full and free exercise of private judgment.

In France, various anarchist currents were present during the Revolutionary period, with some revolutionaries using the term anarchiste in a positive light as early as September 1793.[117] The enrags opposed revolutionary government as a contradiction in terms. Denouncing the Jacobin dictatorship, Jean Varlet wrote in 1794 that “government and revolution are incompatible, unless the people wishes to set its constituted authorities in permanent insurrection against itself”.[118] In his “Manifesto of the Equals”, Sylvain Marchal looked forward to the disappearance, once and for all, of “the revolting distinction between rich and poor, of great and small, of masters and valets, of governors and governed”.[118]

Libertarian socialism, libertarian communism and libertarian Marxism are all phrases which activists with a variety of perspectives have applied to their views.[119] Anarchist communist philosopher Joseph Djacque was the first person to describe himself as a libertarian.[120] Unlike mutualist anarchist philosopher Pierre-Joseph Proudhon, he argued that “it is not the product of his or her labor that the worker has a right to, but to the satisfaction of his or her needs, whatever may be their nature”.[121][122] According to anarchist historian Max Nettlau, the first use of the term “libertarian communism” was in November 1880, when a French anarchist congress employed it to more clearly identify its doctrines.[123] The French anarchist journalist Sbastien Faure started the weekly paper Le Libertaire (The Libertarian) in 1895.[124]

Individualist anarchism refers to several traditions of thought within the anarchist movement that emphasize the individual and their will over any kinds of external determinants such as groups, society, traditions, and ideological systems.[125][126] An influential form of individualist anarchism called egoism[127] or egoist anarchism was expounded by one of the earliest and best-known proponents of individualist anarchism, the German Max Stirner.[128] Stirner’s The Ego and Its Own, published in 1844, is a founding text of the philosophy.[128] According to Stirner, the only limitation on the rights of the individual is their power to obtain what they desire,[129] without regard for God, state or morality.[130] Stirner advocated self-assertion and foresaw unions of egoists, non-systematic associations continually renewed by all parties’ support through an act of will,[131] which Stirner proposed as a form of organisation in place of the state.[132] Egoist anarchists argue that egoism will foster genuine and spontaneous union between individuals.[133] Egoism has inspired many interpretations of Stirner’s philosophy. It was re-discovered and promoted by German philosophical anarchist and LGBT activist John Henry Mackay. Josiah Warren is widely regarded as the first American anarchist,[134] and the four-page weekly paper he edited during 1833, The Peaceful Revolutionist, was the first anarchist periodical published.[135] For American anarchist historian Eunice Minette Schuster, “[i]t is apparent… that Proudhonian Anarchism was to be found in the United States at least as early as 1848 and that it was not conscious of its affinity to the Individualist Anarchism of Josiah Warren and Stephen Pearl Andrews… William B. Greene presented this Proudhonian Mutualism in its purest and most systematic form.”.[136] Later, Benjamin Tucker fused Stirner’s egoism with the economics of Warren and Proudhon in his eclectic influential publication Liberty. From these early influences, individualist anarchism in different countries attracted a small yet diverse following of bohemian artists and intellectuals,[137] free love and birth control advocates (anarchism and issues related to love and sex),[138][139] individualist naturists nudists (anarcho-naturism),[140][141][142] free thought and anti-clerical activists[143][144] as well as young anarchist outlaws in what became known as illegalism and individual reclamation[145][146] (European individualist anarchism and individualist anarchism in France). These authors and activists included Emile Armand, Han Ryner, Henri Zisly, Renzo Novatore, Miguel Gimenez Igualada, Adolf Brand and Lev Chernyi.

In 1873, the follower and translator of Proudhon, the Catalan Francesc Pi i Margall, became President of Spain with a program which wanted “to establish a decentralized, or “cantonalist,” political system on Proudhonian lines”,[147] who according to Rudolf Rocker had “political ideas…much in common with those of Richard Price, Joseph Priestly [sic], Thomas Paine, Jefferson, and other representatives of the Anglo-American liberalism of the first period. He wanted to limit the power of the state to a minimum and gradually replace it by a Socialist economic order”.[148] On the other hand, Fermn Salvochea was a mayor of the city of Cdiz and a president of the province of Cdiz. He was one of the main propagators of anarchist thought in that area in the late 19th century and is considered to be “perhaps the most beloved figure in the Spanish Anarchist movement of the 19th century”.[149][150] Ideologically, he was influenced by Bradlaugh, Owen and Paine, whose works he had studied during his stay in England and Kropotkin, whom he read later.[149] The revolutionary wave of 19171923 saw the active participation of anarchists in Russia and Europe. Russian anarchists participated alongside the Bolsheviks in both the February and October 1917 revolutions. However, Bolsheviks in central Russia quickly began to imprison or drive underground the libertarian anarchists. Many fled to the Ukraine.[151] There, in the Ukrainian Free Territory they fought in the Russian Civil War against the White movement, monarchists and other opponents of revolution and then against Bolsheviks as part of the Revolutionary Insurrectionary Army of Ukraine led by Nestor Makhno, who established an anarchist society in the region for a number of months. Expelled American anarchists Emma Goldman and Alexander Berkman protested Bolshevik policy before they left Russia.[152]

The victory of the Bolsheviks damaged anarchist movements internationally as workers and activists joined Communist parties. In France and the United States, for example, members of the major syndicalist movements of the CGT and IWW joined the Communist International.[153] In Paris, the Dielo Truda group of Russian anarchist exiles, which included Nestor Makhno, issued a 1926 manifesto, the Organizational Platform of the General Union of Anarchists (Draft), calling for new anarchist organizing structures.[154][155]

The Bavarian Soviet Republic of 19181919 had libertarian socialist characteristics.[156][157] In Italy, from 1918 to 1921 the anarcho-syndicalist trade union Unione Sindacale Italiana grew to 800,000 members.[158]

In the 1920s and 1930s, with the rise of fascism in Europe, anarchists began to fight fascists in Italy,[159] in France during the February 1934 riots[160] and in Spain where the CNT (Confederacin Nacional del Trabajo) boycott of elections led to a right-wing victory and its later participation in voting in 1936 helped bring the popular front back to power. This led to a ruling class attempted coup and the Spanish Civil War (19361939).[161] Gruppo Comunista Anarchico di Firenze held that the during early twentieth century, the terms libertarian communism and anarchist communism became synonymous within the international anarchist movement as a result of the close connection they had in Spain (anarchism in Spain) (with libertarian communism becoming the prevalent term).[162]

Murray Bookchin wrote that the Spanish libertarian movement of the mid-1930s was unique because its workers’ control and collectiveswhich came out of a three-generation “massive libertarian movement”divided the republican camp and challenged the Marxists. “Urban anarchists” created libertarian communist forms of organization which evolved into the CNT, a syndicalist union providing the infrastructure for a libertarian society. Also formed were local bodies to administer social and economic life on a decentralized libertarian basis. Much of the infrastructure was destroyed during the 1930s Spanish Civil War against authoritarian and fascist forces.[163] The Iberian Federation of Libertarian Youth[164] (FIJL, Spanish: Federacin Ibrica de Juventudes Libertarias), sometimes abbreviated as Libertarian Youth (Juventudes Libertarias), was a libertarian socialist[165] organisation created in 1932 in Madrid.[166] In February 1937, the FIJL organised a plenum of regional organisations (second congress of FIJL). In October 1938, from the 16th through the 30th in Barcelona the FIJL participated in a national plenum of the libertarian movement, also attended by members of the CNT and the Iberian Anarchist Federation (FAI).[167] The FIJL exists until today. When the republican forces lost the Spanish Civil War, the city of Madrid was turned over to the francoist forces in 1939 by the last non-francoist mayor of the city, the anarchist Melchor Rodrguez Garca.[168] During autumn of 1931, the “Manifesto of the 30” was published by militants of the anarchist trade union CNT and among those who signed it there was the CNT General Secretary (19221923) Joan Peiro, Angel Pestaa CNT (General Secretary in 1929) and Juan Lopez Sanchez. They were called treintismo and they were calling for “libertarian possibilism” which advocated achieving libertarian socialist ends with participation inside structures of contemporary parliamentary democracy.[169] In 1932, they establish the Syndicalist Party which participates in the 1936 spanish general elections and proceed to be a part of the leftist coalition of parties known as the Popular Front obtaining 2 congressmen (Pestaa and Benito Pabon). In 1938, Horacio Prieto, general secretary of the CNT, proposes that the Iberian Anarchist Federation transforms itself into a “Libertarian Socialist Party” and that it participates in the national elections.[170]

The Manifesto of Libertarian Communism was written in 1953 by Georges Fontenis for the Federation Communiste Libertaire of France. It is one of the key texts of the anarchist-communist current known as platformism.[171] In 1968, in Carrara, Italy the International of Anarchist Federations was founded during an international anarchist conference to advance libertarian solidarity. It wanted to form “a strong and organised workers movement, agreeing with the libertarian ideas”.[172][173] In the United States, the Libertarian League was founded in New York City in 1954 as a left-libertarian political organisation building on the Libertarian Book Club.[174][175] Members included Sam Dolgoff,[176] Russell Blackwell, Dave Van Ronk, Enrico Arrigoni[177] and Murray Bookchin.

In Australia, the Sydney Push was a predominantly left-wing intellectual subculture in Sydney from the late 1940s to the early 1970s which became associated with the label “Sydney libertarianism”. Well known associates of the Push include Jim Baker, John Flaus, Harry Hooton, Margaret Fink, Sasha Soldatow,[178] Lex Banning, Eva Cox, Richard Appleton, Paddy McGuinness, David Makinson, Germaine Greer, Clive James, Robert Hughes, Frank Moorhouse and Lillian Roxon. Amongst the key intellectual figures in Push debates were philosophers David J. Ivison, George Molnar, Roelof Smilde, Darcy Waters and Jim Baker, as recorded in Baker’s memoir Sydney Libertarians and the Push, published in the libertarian Broadsheet in 1975.[179] An understanding of libertarian values and social theory can be obtained from their publications, a few of which are available online.[180][181]

In 1969, French platformist anarcho-communist Daniel Gurin published an essay in 1969 called “Libertarian Marxism?” in which he dealt with the debate between Karl Marx and Mikhail Bakunin at the First International and afterwards suggested that “[l]ibertarian marxism rejects determinism and fatalism, giving the greater place to individual will, intuition, imagination, reflex speeds, and to the deep instincts of the masses, which are more far-seeing in hours of crisis than the reasonings of the ‘elites’; libertarian marxism thinks of the effects of surprise, provocation and boldness, refuses to be cluttered and paralysed by a heavy ‘scientific’ apparatus, doesn’t equivocate or bluff, and guards itself from adventurism as much as from fear of the unknown”.[182] Libertarian Marxist currents often draw from Marx and Engels’ later works, specifically the Grundrisse and The Civil War in France.[183] They emphasize the Marxist belief in the ability of the working class to forge its own destiny without the need for a revolutionary party or state.[184] Libertarian Marxism includes such currents as council communism, left communism, Socialisme ou Barbarie, Lettrism/Situationism and operaismo/autonomism and New Left.[185][unreliable source?] In the United States, from 1970 to 1981 there existed the publication Root & Branch[186] which had as a subtitle “A Libertarian Marxist Journal”.[187] In 1974, the Libertarian Communism journal was started in the United Kingdom by a group inside the Socialist Party of Great Britain.[188] In 1986, the anarcho-syndicalist Sam Dolgoff started and led the publication Libertarian Labor Review in the United States[189] which decided to rename itself as Anarcho-Syndicalist Review in order to avoid confusion with right-libertarian views.[190]

The indigenous anarchist tradition in the United States was largely individualist.[191] In 1825, Josiah Warren became aware of the social system of utopian socialist Robert Owen and began to talk with others in Cincinnati about founding a communist colony.[192] When this group failed to come to an agreement about the form and goals of their proposed community, Warren “sold his factory after only two years of operation, packed up his young family, and took his place as one of 900 or so Owenites who had decided to become part of the founding population of New Harmony, Indiana”.[193] Warren termed the phrase “cost the limit of price”[194] and “proposed a system to pay people with certificates indicating how many hours of work they did. They could exchange the notes at local time stores for goods that took the same amount of time to produce”.[195] He put his theories to the test by establishing an experimental labor-for-labor store called the Cincinnati Time Store where trade was facilitated by labor notes. The store proved successful and operated for three years, after which it was closed so that Warren could pursue establishing colonies based on mutualism, including Utopia and Modern Times. “After New Harmony failed, Warren shifted his ideological loyalties from socialism to anarchism (which was no great leap, given that Owen’s socialism had been predicated on Godwin’s anarchism)”.[196] Warren is widely regarded as the first American anarchist[195] and the four-page weekly paper The Peaceful Revolutionist he edited during 1833 was the first anarchist periodical published,[135] an enterprise for which he built his own printing press, cast his own type and made his own printing plates.[135]

Catalan historian Xavier Diez reports that the intentional communal experiments pioneered by Warren were influential in European individualist anarchists of the late 19th and early 20th centuries such as mile Armand and the intentional communities started by them.[197] Warren said that Stephen Pearl Andrews, individualist anarchist and close associate, wrote the most lucid and complete exposition of Warren’s own theories in The Science of Society, published in 1852.[198] Andrews was formerly associated with the Fourierist movement, but converted to radical individualism after becoming acquainted with the work of Warren. Like Warren, he held the principle of “individual sovereignty” as being of paramount importance. Contemporary American anarchist Hakim Bey reports:

Steven Pearl Andrews… was not a fourierist, but he lived through the brief craze for phalansteries in America and adopted a lot of fourierist principles and practices… a maker of worlds out of words. He syncretized abolitionism in the United States, free love, spiritual universalism, Warren, and Fourier into a grand utopian scheme he called the Universal Pantarchy… He was instrumental in founding several ‘intentional communities,’ including the ‘Brownstone Utopia’ on 14th St. in New York, and ‘Modern Times’ in Brentwood, Long Island. The latter became as famous as the best-known fourierist communes (Brook Farm in Massachusetts & the North American Phalanx in New Jersey)in fact, Modern Times became downright notorious (for ‘Free Love’) and finally foundered under a wave of scandalous publicity. Andrews (and Victoria Woodhull) were members of the infamous Section 12 of the 1st International, expelled by Marx for its anarchist, feminist, and spiritualist tendencies.[199]

For American anarchist historian Eunice Minette Schuster, “[it is apparent… that Proudhonian Anarchism was to be found in the United States at least as early as 1848 and that it was not conscious of its affinity to the Individualist Anarchism of Josiah Warren and Stephen Pearl Andrews. William B. Greene presented this Proudhonian Mutualism in its purest and most systematic form”.[200] William Batchelder Greene was a 19th-century mutualist individualist anarchist, Unitarian minister, soldier and promoter of free banking in the United States. Greene is best known for the works Mutual Banking, which proposed an interest-free banking system; and Transcendentalism, a critique of the New England philosophical school. After 1850, he became active in labor reform.[200] “He was elected vice-president of the New England Labor Reform League, the majority of the members holding to Proudhon’s scheme of mutual banking, and in 1869 president of the Massachusetts Labor Union”.[200] Greene then published Socialistic, Mutualistic, and Financial Fragments (1875).[200] He saw mutualism as the synthesis of “liberty and order”.[200] His “associationism… is checked by individualism… ‘Mind your own business,’ ‘Judge not that ye be not judged.’ Over matters which are purely personal, as for example, moral conduct, the individual is sovereign, as well as over that which he himself produces. For this reason he demands ‘mutuality’ in marriagethe equal right of a woman to her own personal freedom and property”.[200]

Poet, naturalist and transcendentalist Henry David Thoreau was an important early influence in individualist anarchist thought in the United States and Europe. He is best known for his book Walden, a reflection upon simple living in natural surroundings; and his essay Civil Disobedience (Resistance to Civil Government), an argument for individual resistance to civil government in moral opposition to an unjust state. In Walden, Thoreau advocates simple living and self-sufficiency among natural surroundings in resistance to the advancement of industrial civilization.[201] Civil Disobedience, first published in 1849, argues that people should not permit governments to overrule or atrophy their consciences and that people have a duty to avoid allowing such acquiescence to enable the government to make them the agents of injustice. These works influenced green anarchism, anarcho-primitivism and anarcho-pacifism,[202] as well as figures including Mohandas Gandhi, Martin Luther King, Jr., Martin Buber and Leo Tolstoy.[202] “Many have seen in Thoreau one of the precursors of ecologism and anarcho-primitivism represented today in John Zerzan. For George Woodcock this attitude can be also motivated by certain idea of resistance to progress and of rejection of the growing materialism which is the nature of American society in the mid-19th century”.[201] Zerzan included Thoreau’s “Excursions” in his edited compilation of anti-civilization writings, Against Civilization: Readings and Reflections.[203] Individualist anarchists such as Thoreau[204][205] do not speak of economics, but simply the right of disunion from the state and foresee the gradual elimination of the state through social evolution. Agorist author J. Neil Schulman cites Thoreau as a primary inspiration.[206]

Many economists since Adam Smith have argued thatunlike other taxesa land value tax would not cause economic inefficiency.[207] It would be a progressive tax[208]primarily paid by the wealthyand increase wages, reduce economic inequality, remove incentives to misuse real estate and reduce the vulnerability that economies face from credit and property bubbles.[209][210] Early proponents of this view include Thomas Paine, Herbert Spencer, and Hugo Grotius,[84] but the concept was widely popularized by the economist and social reformer Henry George.[211] George believed that people ought to own the fruits of their labor and the value of the improvements they make, thus he was opposed to income taxes, sales taxes, taxes on improvements and all other taxes on production, labor, trade or commerce. George was among the staunchest defenders of free markets and his book Protection or Free Trade was read into the U.S. Congressional Record.[212] Yet he did support direct management of natural monopolies as a last resort, such as right-of-way monopolies necessary for railroads. George advocated for elimination of intellectual property arrangements in favor of government sponsored prizes for inventors.[213][not in citation given] Early followers of George’s philosophy called themselves single taxers because they believed that the only legitimate, broad-based tax was land rent. The term Georgism was coined later, though some modern proponents prefer the term geoism instead,[214] leaving the meaning of “geo” (Earth in Greek) deliberately ambiguous. The terms “Earth Sharing”,[215] “geonomics”[216] and “geolibertarianism”[217] are used by some Georgists to represent a difference of emphasis, or real differences about how land rent should be spent, but all agree that land rent should be recovered from its private owners.

Individualist anarchism found in the United States an important space for discussion and development within the group known as the “Boston anarchists”.[218] Even among the 19th-century American individualists there was no monolithic doctrine and they disagreed amongst each other on various issues including intellectual property rights and possession versus property in land.[219][220][221] Some Boston anarchists, including Benjamin Tucker, identified as socialists, which in the 19th century was often used in the sense of a commitment to improving conditions of the working class (i.e. “the labor problem”).[222] Lysander Spooner, besides his individualist anarchist activism, was also an anti-slavery activist and member of the First International.[223] Tucker argued that the elimination of what he called “the four monopolies”the land monopoly, the money and banking monopoly, the monopoly powers conferred by patents and the quasi-monopolistic effects of tariffswould undermine the power of the wealthy and big business, making possible widespread property ownership and higher incomes for ordinary people, while minimizing the power of would-be bosses and achieving socialist goals without state action. Tucker’s anarchist periodical, Liberty, was published from August 1881 to April 1908. The publication, emblazoned with Proudhon’s quote that liberty is “Not the Daughter But the Mother of Order” was instrumental in developing and formalizing the individualist anarchist philosophy through publishing essays and serving as a forum for debate. Contributors included Benjamin Tucker, Lysander Spooner, Auberon Herbert, Dyer Lum, Joshua K. Ingalls, John Henry Mackay, Victor Yarros, Wordsworth Donisthorpe, James L. Walker, J. William Lloyd, Florence Finch Kelly, Voltairine de Cleyre, Steven T. Byington, John Beverley Robinson, Jo Labadie, Lillian Harman and Henry Appleton.[224] Later, Tucker and others abandoned their traditional support of natural rights and converted to an egoism modeled upon the philosophy of Max Stirner.[220] A number of natural rights proponents stopped contributing in protest and “[t]hereafter, Liberty championed egoism, although its general content did not change significantly”.[225] Several publications “were undoubtedly influenced by Liberty’s presentation of egoism. They included: I published by C.L. Swartz, edited by W.E. Gordak and J.W. Lloyd (all associates of Liberty); The Ego and The Egoist, both of which were edited by Edward H. Fulton. Among the egoist papers that Tucker followed were the German Der Eigene, edited by Adolf Brand, and The Eagle and The Serpent, issued from London. The latter, the most prominent English-language egoist journal, was published from 1898 to 1900 with the subtitle ‘A Journal of Egoistic Philosophy and Sociology'”.[225]

By around the start of the 20th century, the heyday of individualist anarchism had passed.[226] H. L. Mencken and Albert Jay Nock were the first prominent figures in the United States to describe themselves as libertarians;[227] they believed Franklin D. Roosevelt had co-opted the word “liberal” for his New Deal policies which they opposed and used “libertarian” to signify their allegiance to individualism.[citation needed] In 1914, Nock joined the staff of The Nation magazine, which at the time was supportive of liberal capitalism. A lifelong admirer of Henry George, Nock went on to become co-editor of The Freeman from 1920 to 1924, a publication initially conceived as a vehicle for the single tax movement, financed by the wealthy wife of the magazine’s other editor, Francis Neilson.[228] Critic H.L. Mencken wrote that “[h]is editorials during the three brief years of the Freeman set a mark that no other man of his trade has ever quite managed to reach. They were well-informed and sometimes even learned, but there was never the slightest trace of pedantry in them”.[229]

Executive Vice President of the Cato Institute, David Boaz, writes: “In 1943, at one of the lowest points for liberty and humanity in history, three remarkable women published books that could be said to have given birth to the modern libertarian movement”.[230] Isabel Paterson’s The God of the Machine, Rose Wilder Lane’s The Discovery of Freedom and Ayn Rand’s The Fountainhead each promoted individualism and capitalism. None of the three used the term libertarianism to describe their beliefs and Rand specifically rejected the label, criticizing the burgeoning American libertarian movement as the “hippies of the right”.[231] Rand’s own philosophy, Objectivism, is notedly similar to libertarianism and she accused libertarians of plagiarizing her ideas.[231] Rand stated:

All kinds of people today call themselves “libertarians,” especially something calling itself the New Right, which consists of hippies who are anarchists instead of leftist collectivists; but anarchists are collectivists. Capitalism is the one system that requires absolute objective law, yet libertarians combine capitalism and anarchism. That’s worse than anything the New Left has proposed. It’s a mockery of philosophy and ideology. They sling slogans and try to ride on two bandwagons. They want to be hippies, but don’t want to preach collectivism because those jobs are already taken. But anarchism is a logical outgrowth of the anti-intellectual side of collectivism. I could deal with a Marxist with a greater chance of reaching some kind of understanding, and with much greater respect. Anarchists are the scum of the intellectual world of the Left, which has given them up. So the Right picks up another leftist discard. That’s the libertarian movement.[232]

In 1946, Leonard E. Read founded the Foundation for Economic Education (FEE), an American nonprofit educational organization which promotes the principles of laissez-faire economics, private property, and limited government.[233] According to Gary North, former FEE director of seminars and a current Ludwig von Mises Institute scholar, FEE is the “granddaddy of all libertarian organizations”.[234] The initial officers of FEE were Leonard E. Read as President, Austrian School economist Henry Hazlitt as Vice-President and Chairman David Goodrich of B. F. Goodrich. Other trustees on the FEE board have included wealthy industrialist Jasper Crane of DuPont, H. W. Luhnow of William Volker & Co. and Robert Welch, founder of the John Birch Society.[236][237]

Austrian school economist Murray Rothbard was initially an enthusiastic partisan of the Old Right, particularly because of its general opposition to war and imperialism,[238] but long embraced a reading of American history that emphasized the role of elite privilege in shaping legal and political institutions. He was part of Ayn Rand’s circle for a brief period, but later harshly criticized Objectivism.[239] He praised Rand’s Atlas Shrugged and wrote that she “introduced me to the whole field of natural rights and natural law philosophy”, prompting him to learn “the glorious natural rights tradition”.[240](pp121, 132134) He soon broke with Rand over various differences, including his defense of anarchism. Rothbard was influenced by the work of the 19th-century American individualist anarchists[241] and sought to meld their advocacy of free markets and private defense with the principles of Austrian economics.[242] This new philosophy he called anarcho-capitalism.

Karl Hess, a speechwriter for Barry Goldwater and primary author of the Republican Party’s 1960 and 1964 platforms, became disillusioned with traditional politics following the 1964 presidential campaign in which Goldwater lost to Lyndon B. Johnson. He parted with the Republicans altogether after being rejected for employment with the party, and began work as a heavy-duty welder. Hess began reading American anarchists largely due to the recommendations of his friend Murray Rothbard and said that upon reading the works of communist anarchist Emma Goldman, he discovered that anarchists believed everything he had hoped the Republican Party would represent. For Hess, Goldman was the source for the best and most essential theories of Ayn Rand without any of the “crazy solipsism that Rand was so fond of”.[243] Hess and Rothbard founded the journal Left and Right: A Journal of Libertarian Thought, which was published from 1965 to 1968, with George Resch and Leonard P. Liggio. In 1969, they edited The Libertarian Forum 1969, which Hess left in 1971. Hess eventually put his focus on the small scale, stating that “Society is: people together making culture”. He deemed two of his cardinal social principles to be “opposition to central political authority” and “concern for people as individuals”. His rejection of standard American party politics was reflected in a lecture he gave during which he said: “The Democrats or liberals think that everybody is stupid and therefore they need somebody… to tell them how to behave themselves. The Republicans think everybody is lazy”.[244]

The Vietnam War split the uneasy alliance between growing numbers of American libertarians and conservatives who believed in limiting liberty to uphold moral virtues. Libertarians opposed to the war joined the draft resistance and peace movements, as well as organizations such as Students for a Democratic Society (SDS). In 1969 and 1970, Hess joined with others, including Murray Rothbard, Robert LeFevre, Dana Rohrabacher, Samuel Edward Konkin III and former SDS leader Carl Oglesby to speak at two “left-right” conferences which brought together activists from both the Old Right and the New Left in what was emerging as a nascent libertarian movement.[245] As part of his effort to unite right and left-libertarianism, Hess would join the SDS as well as the Industrial Workers of the World (IWW), of which he explained: “We used to have a labor movement in this country, until I.W.W. leaders were killed or imprisoned. You could tell labor unions had become captive when business and government began to praise them. They’re destroying the militant black leaders the same way now. If the slaughter continues, before long liberals will be asking, ‘What happened to the blacks? Why aren’t they militant anymore?'”.[246] Rothbard ultimately broke with the left, allying himself instead with the burgeoning paleoconservative movement.[247] He criticized the tendency of these left-libertarians to appeal to “‘free spirits,’ to people who don’t want to push other people around, and who don’t want to be pushed around themselves” in contrast to “the bulk of Americans,” who “might well be tight-assed conformists, who want to stamp out drugs in their vicinity, kick out people with strange dress habits, etc”.[248] This left-libertarian tradition has been carried to the present day by Samuel Edward Konkin III’s agorists, contemporary mutualists such as Kevin Carson and Roderick T. Long and other left-wing market anarchists.[249]

In 1971, a small group of Americans led by David Nolan formed the Libertarian Party,[250] which has run a presidential candidate every election year since 1972. Other libertarian organizations, such as the Center for Libertarian Studies and the Cato Institute, were also formed in the 1970s.[251] Philosopher John Hospers, a one-time member of Rand’s inner circle, proposed a non-initiation of force principle to unite both groups, but this statement later became a required “pledge” for candidates of the Libertarian Party and Hospers became its first presidential candidate in 1972.[citation needed] In the 1980s, Hess joined the Libertarian Party and served as editor of its newspaper from 1986 to 1990.

Modern libertarianism gained significant recognition in academia with the publication of Harvard University professor Robert Nozick’s Anarchy, State, and Utopia in 1974, for which he received a National Book Award in 1975.[252] In response to John Rawls’s A Theory of Justice, Nozick’s book supported a nightwatchman state on the grounds that it was an inevitable phenomenon which could arise without violating individual rights.[253]

In the early 1970s, Rothbard wrote that “[o]ne gratifying aspect of our rise to some prominence is that, for the first time in my memory, we, ‘our side,’ had captured a crucial word from the enemy… ‘Libertarians’… had long been simply a polite word for left-wing anarchists, that is for anti-private property anarchists, either of the communist or syndicalist variety. But now we had taken it over”.[254] Since the resurgence of neoliberalism in the 1970s, this modern American libertarianism has spread beyond North America via think tanks and political parties.[255][256]

A surge of popular interest in libertarian socialism occurred in western nations during the 1960s and 1970s.[257] Anarchism was influential in the Counterculture of the 1960s[258][259][260] and anarchists actively participated in the late sixties students and workers revolts.[261] In 1968, the International of Anarchist Federations was founded in Carrara, Italy during an international anarchist conference held there in 1968 by the three existing European federations of France, the Italian and the Iberian Anarchist Federation as well as the Bulgarian federation in French exile.[173][262] The uprisings of May 1968 also led to a small resurgence of interest in left communist ideas. Various small left communist groups emerged around the world, predominantly in the leading capitalist countries. A series of conferences of the communist left began in 1976, with the aim of promoting international and cross-tendency discussion, but these petered out in the 1980s without having increased the profile of the movement or its unity of ideas.[263] Left communist groups existing today include the International Communist Party, International Communist Current and the Internationalist Communist Tendency. The housing and employment crisis in most of Western Europe led to the formation of communes and squatter movements like that of Barcelona, Spain. In Denmark, squatters occupied a disused military base and declared the Freetown Christiania, an autonomous haven in central Copenhagen.

Around the turn of the 21st century, libertarian socialism grew in popularity and influence as part of the anti-war, anti-capitalist and anti-globalisation movements.[264] Anarchists became known for their involvement in protests against the meetings of the World Trade Organization (WTO), Group of Eight and the World Economic Forum. Some anarchist factions at these protests engaged in rioting, property destruction and violent confrontations with police. These actions were precipitated by ad hoc, leaderless, anonymous cadres known as black blocs and other organisational tactics pioneered in this time include security culture, affinity groups and the use of decentralised technologies such as the internet.[264] A significant event of this period was the confrontations at WTO conference in Seattle in 1999.[264] For English anarchist scholar Simon Critchley, “contemporary anarchism can be seen as a powerful critique of the pseudo-libertarianism of contemporary neo-liberalism…One might say that contemporary anarchism is about responsibility, whether sexual, ecological or socio-economic; it flows from an experience of conscience about the manifold ways in which the West ravages the rest; it is an ethical outrage at the yawning inequality, impoverishment and disenfranchisment that is so palpable locally and globally”.[265] This might also have been motivated by “the collapse of ‘really existing socialism’ and the capitulation to neo-liberalism of Western social democracy”.[266]

Libertarian socialists in the early 21st century have been involved in the alter-globalization movement, squatter movement; social centers; infoshops; anti-poverty groups such as Ontario Coalition Against Poverty and Food Not Bombs; tenants’ unions; housing cooperatives; intentional communities generally and egalitarian communities; anti-sexist organizing; grassroots media initiatives; digital media and computer activism; experiments in participatory economics; anti-racist and anti-fascist groups like Anti-Racist Action and Anti-Fascist Action; activist groups protecting the rights of immigrants and promoting the free movement of people, such as the No Border network; worker co-operatives, countercultural and artist groups; and the peace movement.

In the United States, polls (circa 2006) find that the views and voting habits of between 10 and 20 percent (and increasing) of voting age Americans may be classified as “fiscally conservative and socially liberal, or libertarian”.[267][268] This is based on pollsters and researchers defining libertarian views as fiscally conservative and socially liberal (based on the common United States meanings of the terms) and against government intervention in economic affairs and for expansion of personal freedoms.[267] Through 20 polls on this topic spanning 13 years, Gallup found that voters who are libertarian on the political spectrum ranged from 1723% of the United States electorate.[269] However, a 2014 Pew Poll found that 23% of Americans who identify as libertarians have no idea what the word means.[270]

2009 saw the rise of the Tea Party movement, an American political movement known for advocating a reduction in the United States national debt and federal budget deficit by reducing government spending and taxes, which had a significant libertarian component[271] despite having contrasts with libertarian values and views in some areas, such as nationalism, free trade, social issues and immigration.[272] A 2011 Reason-Rupe poll found that among those who self-identified as Tea Party supporters, 41 percent leaned libertarian and 59 percent socially conservative.[273] The movement, named after the Boston Tea Party, also contains conservative[274] and populist elements[275] and has sponsored multiple protests and supported various political candidates since 2009. Tea Party activities have declined since 2010 with the number of chapters across the country slipping from about 1,000 to 600.[276][277] Mostly, Tea Party organizations are said to have shifted away from national demonstrations to local issues.[276] Following the selection of Paul Ryan as Mitt Romney’s 2012 vice presidential running mate, The New York Times declared that Tea Party lawmakers are no longer a fringe of the conservative coalition, but now “indisputably at the core of the modern Republican Party”.[278]

In 2012, anti-war presidential candidates (Libertarian Republican Ron Paul and Libertarian Party candidate Gary Johnson) raised millions of dollars and garnered millions of votes despite opposition to their obtaining ballot access by Democrats and Republicans.[279] The 2012 Libertarian National Convention, which saw Gary Johnson and James P. Gray nominated as the 2012 presidential ticket for the Libertarian Party, resulted in the most successful result for a third-party presidential candidacy since 2000 and the best in the Libertarian Party’s history by vote number. Johnson received 1% of the popular vote, amounting to more than 1.2 million votes.[280][281] Johnson has expressed a desire to win at least 5 percent of the vote so that the Libertarian Party candidates could get equal ballot access and federal funding, thus subsequently ending the two-party system.[282][283][284]

Since the 1950s, many American libertarian organizations have adopted a free market stance, as well as supporting civil liberties and non-interventionist foreign policies. These include the Ludwig von Mises Institute, Francisco Marroqun University, the Foundation for Economic Education, Center for Libertarian Studies, the Cato Institute and Liberty International. The activist Free State Project, formed in 2001, works to bring 20,000 libertarians to New Hampshire to influence state policy.[285] Active student organizations include Students for Liberty and Young Americans for Liberty.

A number of countries have libertarian parties that run candidates for political office. In the United States, the Libertarian Party was formed in 1972 and is the third largest[286][287] American political party, with over 370,000 registered voters in the 35 states that allow registration as a Libertarian[288] and has hundreds of party candidates elected or appointed to public office.[289]

Current international anarchist federations which sometimes identify themselves as libertarian include the International of Anarchist Federations, the International Workers’ Association, and International Libertarian Solidarity. The largest organised anarchist movement today is in Spain, in the form of the Confederacin General del Trabajo (CGT) and the CNT. CGT membership was estimated to be around 100,000 for 2003.[290] Other active syndicalist movements include the Central Organisation of the Workers of Sweden and the Swedish Anarcho-syndicalist Youth Federation in Sweden; the Unione Sindacale Italiana in Italy; Workers Solidarity Alliance in the United States; and Solidarity Federation in the United Kingdom. The revolutionary industrial unionist Industrial Workers of the World claiming 2,000 paying members as well as the International Workers Association, an anarcho-syndicalist successor to the First International, also remain active. In the United States, there exists the Common Struggle Libertarian Communist Federation.

Criticism of libertarianism includes ethical, economic, environmental, pragmatic, and philosophical concerns.[291] It has also been argued that laissez-faire capitalism does not necessarily produce the best or most efficient outcome,[292] nor does its policy of deregulation prevent the abuse of natural resources. Furthermore, libertarianism has been criticized as utopian due to the lack of any such societies today.

Critics such as Corey Robin describe right-libertarianism as fundamentally a reactionary conservative ideology, united with more traditional conservative thought and goals by a desire to enforce hierarchical power and social relations:[293]

Conservatism, then, is not a commitment to limited government and libertyor a wariness of change, a belief in evolutionary reform, or a politics of virtue. These may be the byproducts of conservatism, one or more of its historically specific and ever-changing modes of expression. But they are not its animating purpose. Neither is conservatism a makeshift fusion of capitalists, Christians, and warriors, for that fusion is impelled by a more elemental forcethe opposition to the liberation of men and women from the fetters of their superiors, particularly in the private sphere. Such a view might seem miles away from the libertarian defense of the free market, with its celebration of the atomistic and autonomous individual. But it is not. When the libertarian looks out upon society, he does not see isolated individuals; he sees private, often hierarchical, groups, where a father governs his family and an owner his employees.

John Donahue argues that if political power were radically shifted to local authorities, parochial local interests would predominate at the expense of the whole and that this would exacerbate current problems with collective action.[294]

Michael Lind has observed that of the 195 countries in the world today, none have fully actualized a libertarian society:

If libertarianism was a good idea, wouldn’t at least one country have tried it? Wouldn’t there be at least one country, out of nearly two hundred, with minimal government, free trade, open borders, decriminalized drugs, no welfare state and no public education system?[295]

Lind has also criticised libertarianism, particularly the right-wing and free market variant of the ideology, as being incompatible with democracy and apologetic towards autocracy.[296]

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Libertarianism – Wikipedia

6 Reasons Why I Gave Up On Libertarianism Return Of Kings

These days, libertarianism tends to be quite discredited. It is now associated with the goofy candidature of Gary Johnson, having a rather narrow range of issueslegalize weed! less taxes!, cucking ones way to politics through sweeping all the embarrassing problems under the carpet, then surrendering to liberal virtue-signaling and endorsing anti-white diversity.

Now, everyone on the Alt-Right, manosphere und so wieser is laughing at those whose adhesion to a bunch of abstract premises leads to endorse globalist capital, and now that Trump officially heads the State, wed be better off if some private companies were nationalized than let to shadowy overlords.

To Americans, libertarianism has been a constant background presence. Its main icons, be them Ayn Rand, Murray Rothbard or Friedrich Hayek, were always read and discussed here and there, and never fell into oblivion although they barely had media attention. The academic and political standing of libertarianism may be marginal, it has always been granted small platforms and resurrected from time to time in the public landscape, one of the most conspicuous examples of it being the Tea Party demonstrations.

To a frog like yours trulyKek being now praised by thousands of well-meaning memers, I can embrace the frog moniker gladlylibertarianism does not have the same standing at all. In French universities, libertarian thinkers are barely discussed, even in classes that are supposed to tackle economics: for one hour spent talking about Hayek, Keynes easily enjoys ten, and the same goes on when comparing the attention given to, respectively, Adam Smith and Karl Marx.

On a wider perspective, a lot of the contemporary French identity is built on Jacobinism, i.e. on crushing underfoot organic regional sociability in the name of a bureaucratized and Masonic republic. The artificial construction of France is exactly the kind of endeavour libertarianism loathes. No matter why the public choices school, for example, is barely studied here: pompous leftist teachers and mediocre fonctionnaires are too busy gushing about themselves, sometimes hiding the emptiness of their life behind a ridiculous epic narrative that turns social achievements into heroic feats, to give a fair hearing to pertinent criticism.

When I found out about libertarianism, I was already sick of the dominant fifty shades of leftism political culture. The gloomy mediocrity of small bureaucrats, including most school teachers, combined with their petty political righteousness, always repelled me. Thus, the discovery oflaissez-faire advocates felt like stumbling on an entirely new scene of thoughtand my initial feeling was vindicated when I found about the naturalism often associated with it, something refreshing and intuitively more satisfying than the mainstream culture-obsessed, biology-denying view.

Libertarianism looked like it could solve everything. More entrepreneurship, more rights to those who actually create wealth and live through the good values of personal responsibility and work ethic, less parasitesbe they bureaucrats or immigrants, no more repressive speech laws. Coincidentally, a new translation of Ayn Rands Atlas Shrugged was published at this time: I devoured it, loving the sense of life, the heroism, the epic, the generally great and achieving ethos contained in it. Arent John Galt and Hank Rearden more appealing than any corrupt politician or beta bureaucrat that pretends to be altruistic while backstabbing his own colleagues and parasitizing the country?

Now, although I still support small-scale entrepreneurship wholeheartedly, I would never defend naked libertarianism, and here is why.

Part of the Rothschild family, where nepotism and consanguinity keep the money in

Unity makes strength, and trust is much easier to cultivate in a small group where everyone truly belongs than in an anonymous great society. Some ethnic groups, especially whites, tend to be instinctively individualistic, with a lot of people favouring personal liberty over belonging, while others, especially Jews, tend to favor extended family business and nepotism.

On a short-term basis, mobile individuals can do better than those who are bound to many social obligations. On the long run, however, extended families manage to create an environment of trust and concentrate capital. And whereas individuals may start cheating each other or scattering their wealth away, thanks to having no proper economic network, families and tribes will be able to invest heavily in some of their members and keep their wealth inside. This has been true for Jewish families, wherever their members work as moneylenders or diamond dealers, for Asians investing in new restaurants or any other business project of their own, and for North Africans taking over pubs and small shops in France.

The latter example is especially telling. White bartenders, butchers, grocers and the like have been chased off French suburbs by daily North African and black violence. No one helped them, everyone being afraid of getting harassed as well and busy with their own business. (Yep, just like what happened and still happens in Rotheram.) As a result, these isolated, unprotected shop-owners sold their outlet for a cheap price and fled. North Africans always covered each others violence and replied in groups against any hurdle, whereas whites lowered their heads and hoped not to be next on the list.

Atlas Shrugged was wrong. Loners get wrecked by groups. Packs of hyenas corner and eat the lone dog.

Libertarianism is not good for individuals on the long runit turns them into asocial weaklings, soon to be legally enslaved by global companies or beaten by groups, be they made of nepotistic family members or thugs.

How the middle classes end up after jobs have been sent overseas and wages lowered

People often believe, thanks to Leftist media and cuckservative posturing, that libertarians are big bosses. This is mostly, if not entirely, false. Most libertarians are middle class guys who want more opportunities, less taxation, and believe that libertarianism will help them to turn into successful entrepreneurs. They may be right in very specific circumstances: during the 2000s, small companies overturned the market of electronics, thus benefiting both to their independent founders and to society as a whole; but ultimately, they got bought by giants like Apple and Google, who are much better off when backed by a corrupt State than on a truly free market.

Libertarianism is a fake alternative, just as impossible to realize as communism: far from putting everyone at its place, it lets ample room to mafias, monopolies, unemployment caused by mechanization and global competition. If one wants the middle classes to survive, one must protect the employment and relative independence of its membersbankers and billionaires be damned.

Spontaneous order helped by a weak government. I hope they at least smoke weed.

A good feature of libertarianism is that it usually goes along with a positive stance on biology and human nature, in contrast with the everything is cultural and ought to be deconstructed left. However, this stance often leads to an exaggerated optimism about human nature. In a society of laissez-faire, the libertarians say, people flourish and the order appears spontaneously.

Well, this is plainly false. As all of the great religions say, after what Christians call the Fall, man is a sinner. If you let children flourish without moral standards and role models, they become spoiled, entitled, manipulative, emotionally fragile and deprived of self-control. If you let women flourish without suspicion, you let free rein to their propensities to hypergamy, hysteria, self-entitlement and everything we can witness in them today. If you let men do as they please, you let them become greedy, envious, and turning into bullies. As a Muslim proverb says, people must be flogged to enter into paradiseand as Aristotle put forth, virtues are trained dispositions, no matter the magnitude of innate talents and propensities.

Michelle The Man Obama and Lying Crooked at a Democrat meeting

When the laissez-faire rules, some will succeed on the market more than others, due to differences in investment, work, and natural abilities. Some will succeed enough to be able to buy someone elses business: this is the natural consequence of differences in wealth and of greed. When corrupt politicians enter the game, things become worse, as they will usually help some large business owners to shield their position against competitorsat the expense of most people, who then lose their independence and live off a wage.

At the end, what we get is a handful of very wealthy individuals who have managed to concentrate most capital and power levers into their hands and a big crowd of low-wage employees ready to cut each others throat for a small promotion, and females waiting in line to get notched by the one per cent while finding the other ninety-nine per cent boring.

Censorship by massive social pressure, monopoly over the institutions and crybullying is perfectly legal. What could go wrong?

On the surface, libertarianism looks good here, because it protects the individuals rights against left-hailing Statism and cuts off the welfare programs that have attracted dozens of millions of immigrants. Beneath, however, things are quite dire. Libertarianism enshrines the leftists right to free speech they abuse from, allows the pressure tactics used by radicals, and lets freethinking individuals getting singled out by SJWs as long as these do not resort to overt stealing or overt physical violence. As for the immigrants, libertarianism tends to oppose the very notion of non-private boundaries, thus letting the local cultures and identities defenseless against both greedy capitalists and subproletarian masses.

Supporting an ideology that allows the leftists to destroy society more or less legally equates to cucking, plain and simple. Desiring an ephemeral cohabitation with rabid ideological warriors is stupid. We should aim at a lasting victory, not at pretending to constrain them through useless means.

Am I the only one to find that Gary Johnson looks like a snail (Spongebob notwithstanding)?

In 2013, one of the rare French libertarians academic teachers, Jean-Louis Caccomo, was forced into a mental ward at the request of his university president. He then spent more than a year getting drugged. Mr. Caccomo had no real psychological problem: his confinement was part of a vicious strategy of pathologization and career-destruction that was already used by the Soviets. French libertarians could have wide denounced the abuse. Nonetheless, most of them freaked out, and almost no one dared to actually defend him publicly.

Why should rational egoists team up and risk their careers to defend one of themselves after all? They would rather posture at confidential social events, rail at organic solidarity and protectionism, or trolling the shit out of individuals of their own social milieu because Ive got the right to mock X, its my right to free speech! The few libertarian people I knew firsthand, the few events I have witnessed in that small milieu, were enough to give me serious doubts about libertarianism: how can a good political ideology breed such an unhealthy mindset?

Political ideologies are tools. They are not ends in themselves. All forms of government arent fit for any people or any era. Political actors must know at least the most important ones to get some inspiration, but ultimately, said actors win on the ground, not in philosophical debates.

Individualism, mindless consumerism, careerism, hedonism are part of the problem. Individual rights granted regardless of ones abilities, situation, and identity are a disaster. Time has come to overcome modernity, not stall in one of its false alternatives. The merchant caste must be regulated, though neither micromanaged or hampered by a parasitic bureaucracy nor denied its members right for small-scale independence. Individual rights must be conditional, boundaries must be restored, minority identities based on anti-white male resentment must be crushed so they cannot devour sociability from the inside again, and the pater familias must assert himself anew.

Long live the State and protectionism as long as they defend the backbone of society and healthy relationships between the sexes, and no quarter for those who think they have a right to wage grievance-mongering against us, no matter if they want to use the State or private companies. At the end, the socialism-libertarianism dichotomy is quite secondary.

Read Next: Sugar Baby Culture In The US Is Creating A Marketplace for Prostitution

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6 Reasons Why I Gave Up On Libertarianism Return Of Kings

Can Libertarianism Be a Governing Philosophy?

The discussion we are about to have naturally divides itself into two aspects:

First: Could libertarianism, if implemented, sustain a state apparatus and not devolve into autocracy or anarchy? By that I mean the lawless versions of autocracy and anarchy, not stable monarchy or emergent rule of law without a state. Second: even if the answer were Yesor, Yes, if . . . we would still need to know whether enough citizens desired a libertarian order that it could feasibly be voluntarily chosen. That is, I am ruling out involuntary imposition by force of libertarianism as a governing philosophy.

I will address both questions, but want to assert at the outset that the first is the more important and more fundamental one. If the answer to it is No, there is no point in moving on to the second question. If the answer is Yes, it may be possible to change peoples minds about accepting a libertarian order.

The Destinationalists

As I have argued elsewhere[1], there are two main paths to deriving libertarian principles, destinations and directions. The destinationist approach shares the method of most other ethical paradigms: the enunciation of timeless moral and ethical precepts that describe the ideal libertarian society.

What makes for a distinctly libertarian set of principles is two precepts:

The extreme forms of these principles, for destinationists, can be hard for outsiders to accept. One example is noted by Matt Zwolinski, who cites opinion data gathered from libertarians by Liberty magazine and presented in its periodic Liberty Poll. A survey question frequently included in the survey was:

Suppose that you are on a friends balcony on the 50th floor of a condominium complex. You trip, stumble and fall over the edge. You catch a flagpole on the next floor down. The owner opens his window and demands you stop trespassing.

Zwolinski writes that in 1988, 84 percent of respondents to the flagpole question

said they believed that in such circumstances they should enter the owners residence against the owners wishes. 2% (one respondent) said that they should let go and fall to their death, and 15% said they should hang on and wait for somebody to throw them a rope. In 1999, the numbers were 86%, 1%, and 13%. In 2008, they were 89.2%, 0.9%, and 9.9%.

The interesting thing is that, while the answers to the flagpole question were almost unchanged over time, with a slight upward drift in those who would aggress by trespassing, support for the non-aggression principle itself plummeted. Writes Zwolinski:

Respondents were asked to say whether they agreed or disagreed with [the non-aggression principle]. In 1988, a full 90% of respondents said that they agreed. By 1999, however, the percentage expressing agreement had dropped by almost half to 50%. And by 2008, it was down to 39.7%.

If we take support for the non-aggression principle as a Rorschach test, it does not appear that most people, maybe not even everyone who identifies as a libertarian, are fully convinced that the principle is an absolute categorical moral principle.

The Directionalists

Of course, it could be true that many who identify now as libertarians, and those who might be attracted to libertarianism in the future, are directionalists. A directional approach holds that any policy action that increases the liberty and welfare of individuals is an improvement, and should be supported by libertarians, even if the policy itself violates either the self-ownership principle or the non-aggression principle.

A useful example here might be school vouchers. Instead of being a monopoly provider of public school education, the state might specialize in funding but leave the provision of education at least partly to private sector actors. The destinationist would object (and correctly) that the policy still involves the initiation of violence in collecting taxes involuntarily imposed on at least individuals who would not pay without the threat of coercion. In contrast, the directionalist might support vouchers, since parents would at least be afforded more liberty in choosing schools for their children, and the system would be subject to more competition, thus holding providers responsible for the quality of education being delivered.

Here, then, is a slightly modified take on the central question: Would a hybrid version of libertarianism, one that advocated for the destination but accepted directional improvements, be a viable governing philosophy? Even with this amendment, allowing for directional improvements as part of the core governing philosophy, is libertarianismto use a trope of the momentsustainable? The reason this approach could be useful is that it correlates to one of the great divisions within the libertarian movement: the split between political anarchists, who believe that any coercive state apparatus is ultimately incompatible with liberty, and the minarchists, who believe that a limited government is desirable, even necessary, and that it is also possible.

Limiting Leviathan: Getting Power to Stay Where You Put It

For a state to be consistent with both the self-ownership principle and the non-aggression principle, there must be certain core rights to property, expression, and action that are inviolable. This inviolability extends even to situations where initiating force would greatly benefit most people, meaning that consequentialist considerations cannot outweigh the rights of individuals.

Where might such a state originate, and how could it be continually limited to only those functions for which it was originally justified? One common answer is a form of contractarianism. (Another is convention, which is beyond the scope in this essay. See Robert Sugden[2] and Gerard Gaus[3] for a review of some of the issues.) This is not to say that actual states are the results of explicitly contractual arrangements; rather, there is an as if element: rational citizens in a state of nature would have voluntarily consented to the limited coercion of a minarchist state, given the substantial and universal improvement in welfare that results from having a provider of public goods and a neutral enforcer of contracts. Without a state, claims the minarchist, these two functionspublic goods provision and contract enforcementare either impossible or so difficult as to make the move to create a coercive state universally welcome for all citizens.

Contractarianism is of course an enormous body of work in philosophy, ranging from Thomas Hobbes and Jean-Jacques Rousseau to David Gauthier and John Rawls. Our contractarians, the libertarian versions, start with James Buchanan and Jan Narveson. Buchanans contractarianism is stark: Rules start with us, and the justification for coercion is, but can only be, our consent to being coerced. It is not clear that Buchanan would accept the full justification of political authority by tacit contract, but Buchanan also claims that each group in society should start from where we are now, meaning that changes in the rules require something as close to unanimous consent as possible.[4]

Narvesons view is closer to the necessary evil claim for justifying government. We need a way to be secure from violence, and to be able to enter into binding agreements that are enforceable. He wrote in The Libertarian Idea (1988) that there is no alternative that can provide reasons to everyone for accepting it, no matter what their personal values or philosophy of life may be, and thus motivating this informal, yet society-wide institution. He goes on to say:

Without resort to obfuscating intuitions, of self-evident rights and the like, the contractarian view offers an intelligible account both of why it is rational to want a morality and of what, broadly speaking, the essentials of that morality must consist in: namely, those general rules that are universally advantageous to rational agents. We each need morality, first because we are vulnerable to the depredations of others, and second because we can all benefit from cooperation with others. So we need protection, in the form of the ability to rely on our fellows not to engage in activities harmful to us; and we need to be able to rely on those with whom we deal. We each need this regardless of what else we need or value.

The problem, or so the principled political anarchist would answer, is that Leviathan cannot be limited unless for some reason Leviathan wants to limit itself.

One of the most interesting proponent of this view is Anthony de Jasay, an independent philosopher of political economy. Jasay would not dispute the value of credible commitments for contracts. His quarrel comes when contractarians invoke a founding myth. When I think of the Social Contract (the capitals signify how important it is!), I am reminded of that scene from Monty Python where King Arthur is talking to the peasants:

King Arthur: I am your king.

Woman: Well, I didnt vote for you.

King Arthur: You dont vote for kings.

Woman: Well howd you become king then?

[holy music . . . ]

King Arthur: The Lady of the Lake, her arm clad in the purest shimmering samite held aloft Excalibur from the bosom of the water, signifying by divine providence that I, Arthur, was to carry Excalibur. That is why I am your king.

Dennis: [interrupting] Listen, strange women lyin in ponds distributin swords is no basis for a system of government. Supreme executive power derives from a mandate from the masses, not from some farcical aquatic ceremony.

According to Jasay, there are two distinct problems with contractarian justifications for the state. Each, separately and independently, is fatal for the project, in his view. Together they put paid to the notion that a libertarian could favor minarchism.

The first problem is the enforceable contracts justification. The second is the limiting Leviathan problem.

The usual statement of the first comes from Hobbes: Covenants, without the sword, are but words. That means that individuals cannot enter into binding agreements without some third party to enforce the agreement. Since entering into binding agreements is a central precondition for mutually beneficial exchange and broad-scale market cooperation, we need a powerful, neutral enforcer. So, we all agree on that; the enforcer collects the taxes that we all agreed on and, in exchange, enforces all our contracts for us. (See John Thrasher[5] for some caveats.)

Butwait. Jasay compares this to jumping over your own shadow. If contracts cannot be enforced save by coercion from a third party, how can the contract between citizens and the state be enforced? [I]t takes courage to affirm that rational people could unanimously wish to have a sovereign contract enforcer bound by no contract, wrote Jasay in his book Against Politics (1997). By courage he does not intend a compliment. Either those who make this claim are contradicting themselves (since we cant have contracts, well use a contract to solve the problem) or the argument is circular (cooperation requires enforceable contracts, but these require a norm of cooperation).

Jasay put the question this way in On Treating Like Cases Alike: Review of Politics by Principle Not Interest, his 1999 essay in the Independent Review:

If man can no more bind himself by contract than he can jump over his own shadow, how can he jump over his own shadow and bind himself in a social contract? He cannot be both incapable of collective action and capable of it when creating the coercive agency needed to enforce his commitment. One can, without resorting to a bootstrap theory, accept the idea of an exogenous coercive agent, a conqueror whose regime is better than anything the conquered people could organize for themselves. Consenting to such an accomplished fact, however, can hardly be represented as entering into a contract, complete with a contracts ethical implications of an act of free will. [Emphasis in original]

In sum, the former claimthat contracts cannot be enforcedcannot then be used to conjure enforceable contracts out of a shadow. The latter claimthat people will cooperate on their ownmeans that no state is necessary in the first place. The conclusion Jasay reaches is that states, if they exist, may well be able to compel people to obey. The usual argument goes like this:

The state exists and enjoys the monopoly of the use of force for some reason, probably a historical one, that we need not inquire into. What matters is that without the state, society could not function tolerably, if at all. Therefore all rational persons would choose to enter into a social contract to create it. Indeed, we should regard the state as if it were the result of our social contract, hence indisputably legitimate.[6]

Jasay concludes that this argument must be false. As Robert Nozick famously put it in Anarchy, State, and Utopia (1974), tacit consent isnt worth the paper its not written on. We cannot confect a claim that states deserve our obedience based on consent. For consent is what true political authority requires: not that our compliance can be compelled, but that the state deserves our compliance. Ordered anarchy with no formal state is therefore a better solution, in Jasays view, because consent is either not real or is not enough.

Of course, this is simply an extension of a long tradition in libertarian thought, dating at least to Lysander Spooner. As Spooner said:

If the majority, however large, of the people of a country, enter into a contract of government, called a constitution, by which they agree to aid, abet or accomplish any kind of injustice, or to destroy or invade the natural rights of any person or persons whatsoever, whether such persons be parties to the compact or not, this contract of government is unlawful and voidand for the same reason that a treaty between two nations for a similar purpose, or a contract of the same nature between two individuals, is unlawful and void. Such a contract of government has no moral sanction. It confers no rightful authority upon those appointed to administer it. It confers no legal or moral rights, and imposes no legal or moral obligation upon the people who are parties to it. The only duties, which any one can owe to it, or to the government established under color of its authority, are disobedience, resistance, destruction.[7]

Now for the other problem highlighted by Jasay, that of limiting Leviathan. Let us assume the best of state officials: that they genuinely intend to do good. We might make the standard Public Choice assumption that officials want to use power to benefit themselves, but let us put that aside; instead, officials genuinely want to improve the lives of their citizens.

This means a minarchist state is not sustainable. Officials, thinking of the society as a collective rather than as individuals with inviolable rights, will immediately discover opportunities to raise taxes, and create new programs and new powers that benefit those in need. In fact, it is precisely the failure of the Public Choice assumptions of narrow self-interest that ensure this outcome. It might be possible in theory to design a principal-agent system of bureaucratic contract that constrains selfish officials. But if state power attracts those who are willing to sacrifice the lives or welfare of some for the greater good, then minarchy is quickly breached and Leviathan swells without the possibility of constraint.

I hasten to add that it need not be true, for Jasays claim to go through, that the concept of the greater good have any empirical content. It is enough that a few people believe, and can brandish the greater good like a truncheon, smashing rules and laws designed to stop the expansion of state power. No one who wants to do good will pass up a chance to do good, even if it means changing the rules. This process is much like that described by F.A. Hayek in Why the Worst Get on Top (see Chapter 10 of The Road to Serfdom) or Bertrand de Jouvenels Power (1945).

So, again, we reach a contradiction: Either 1) minarchy is not possible, because it is overwhelmed by the desire to do good, or minarchy is not legitimate because it is based on a mythical tacit consent; or 2) no state, minarchist or otherwise, is necessary because people can limit their actions on their own. Citizens might conclude that such self-imposed limits on their own actions are morally required, and that reputation and competition can limit the extent of depredation and reward cooperation in settings with repeated interaction. Jasay would argue, then, that constitutions and parchment barriers are either unnecessary (if people are self-governing) or ineffective (if they are not). Leviathan either cannot exist or else it is illimitable.

But Thats Not Enough

What I have argued so far is that destinationist libertarianism that is fully faithful to the self-ownership principle and the non-aggression principle could not be an effective governing philosophy. The only exception to this claim would be if libertarianism were universally believed, and people all agreed to govern themselves in the absence of a coercive state apparatus of any kind. Of course, one could object that even then something like a state would emerge, because of the economies of scale in the provision of defense, leading to a dominant protection network as described by Nozick. Whether that structure of service-delivery is necessarily a state is an interesting question, but not central to our current inquiry.

My own view is that libertarianism is, and in fact should be, a philosophy of governing that is robust and useful. But then I am a thoroughgoing directionalist. The state and its deputized coercive instruments have expanded the scope and intensity of their activities far beyond what people need to achieve cooperative goals, and beyond what they want in terms of immanent intrusions into our private lives.

Given the constant push and pull of politics, and the desire of groups to create and maintain rents for themselves, the task of leaning into the prevailing winds of statism will never be done. But it is a coherent and useful governing philosophy. When someone asks how big the state should be, there arent many people who think the answer is zero. But thats not on the table, anyway. My answer is smaller than it is now. Any policy change that grants greater autonomy (but also responsibility) to individual citizens, or that lessens government control over private action, is desirable; and libertarians are crucial for providing compelling intellectual justifications for why this is so.

In short, I dont advocate abandoning destinationist debates. The positing of an ideal is an important device for recruitment and discussion. But at this point we have been going in the wrong direction, for decades. It should be possible to find allies and fellow travelers. They may want to get off the train long before we arrive at the end of the line, but for many miles our paths toward smaller government follow the same track.

[1] Michael Munger, Basic Income Is Not an Obligation, but It Might Be a Legitimate Choice, Basic Income Studies 6:2 (December 2011), 1-13.

[2] Robert Sugden, Can a Humean Be a Contractarian? in Perspectives in Moral Science, edited by Michael Baurmann and Bernd Lahno, Frankfurt School Verlag (2009), 1123.

[3] Gerald Gaus, Why the Conventionalist Needs the Social Contract (and Vice Versa), Rationality, Markets and Morals, Frankfurt School Verlag, 4 (2013), 7187.

[4] For more on the foundation of Buchanans thought, see my forthcoming essay in the Review of Austrian Economics, Thirty Years After the Nobel: James Buchanans Political Philosophy.

[5] John Thrasher, Uniqueness and Symmetry in Bargaining Theories of Justice, Philosophical Studies 167 (2014), 683699.

[6] Anthony de Jasay, Pious Lies: The Justification of States and Welfare States, Economic Affairs 24:2 (2004), 63-64.

[7] Lysander Spooner, The Unconstitutionality of Slavery (Boston: Bela Marsh, 1860), pp. 9-10.

Original post:

Can Libertarianism Be a Governing Philosophy?

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147] CRISPR gene editing technology has also been used on mice to treat deafness due to the DFNA36 mutation, which also affects humans.[148]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[149] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[150]

Athletes might adopt gene therapy technologies to improve their performance.[151] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[152]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[153][154][155] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[156][157] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[158]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[159]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[160] and such concerns have continued as technology progressed.[161][162] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[149][163] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[164][165] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[166]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[167]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[168]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[169] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[170] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[169]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[171][172]

Gene therapy is the basis for the plotline of the film I Am Legend[173] and the TV show Will Gene Therapy Change the Human Race?.[174] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[175]

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Gene therapy – Wikipedia

Gene Therapy Net – News, Conferences, Vectors, Literature …

Posted on: 22 March 2018, source: GizmodoOn Tuesday, a 13-year-old boy from New Jersey was at the center of medical history as he became the first person in the US to receive an FDA-approved gene therapy for an inherited disease. The event marks the beginning of a new era of medicine, one in which devastating genetic conditions that we are born with can be simply edited out of our DNA with the help of modern biomedical technologies. The therapy, Luxturna, from Spark Therepeutics, was approved by the FDA in December to treat a rare, inherited form of blindness. Its price tag, set at $850,000or $425,000 per eyemade it the most expensive drug in the US and sparked mass sticker-shock. But the therapy, which in high-profile clinical trials has allowed patients to see the stars for the first times, also offered the almost miraculous possibility of giving sight to the blind.

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Gene Therapy Net – News, Conferences, Vectors, Literature …

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body’s cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body’s form and function, from making you grow taller to regulating your body systems. Genes that don’t work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body’s ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can’t easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren’t the only vectors that can be used to carry altered genes into your body’s cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 29, 2017

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Gene therapy – Mayo Clinic


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