The human heart has an innate capacity to remodel in response to advancing coronary artery disease. As plaque builds up in the hearts three major arteries, some genetically privileged patients begin to grow small collateral blood vessels to overcome restricted blood flow and improve cardiac perfusion. This process is known as cardiac angiogenesis. With the passage of time, this response is overrun by disease progression.

Researchers have long wondered if this primal angiogenic healing response could be amplified and regulated through the design and development of angiogenic therapeutics. In recent years, monoclonal antibody therapies have proven effective at harnessing the human bodys natural biological mechanisms to treat cancer. Similarly, within cardiac care, angiogenic gene therapy has shown great promise.

In the U.S., more than one million patients with advanced coronary artery disease suffer from recurrent and severe chest pain, which profoundly limits their physical activity and quality of life. These refractory angina patients are no longer responsive to anti-anginal medications and are either not candidates for stent implantation or bypass surgery, or continue to suffer from angina even after these mechanical revascularization procedures. While drug and proteins appear unsuitable, new research and clinical studies focused on angiogenic gene therapy are now showing great promise as a one-time treatment for more than one million patients in the U.S. with advanced coronary artery disease and refractory angina.

The successful commercialization of an angiogenic gene therapy will require (1) an angiogenic growth factor that regulates the multiple proteins required to orchestrate micro-vessel growth and enlargement; (2) a simple percutaneous catheter-based delivery system to deliver the angiogenic gene therapy into heart cells; and (3) a deep understanding and characterization of patients who are most likely to benefit from angiogenic gene therapy, enabling design of a clinical study properly powered to detect treatment effects and assess potential risk-benefit.

Choice of Angiogenic Growth Factor

One key element of successful gene therapy is gene expression in the targeted cells, at a functional level. For angiogenic gene therapy, a central challenge has been identifying the growth factors that can stimulate the complex angiogenic biological process. It has been debated and widely studied whether the delivery of vascular endothelial growth factor (VEGF) or other growth factors, alone or in combination, is ideal for collateral vessel development. Recent research suggests a more fruitful approach may be the use of a specific regulatory gene, FGF-4, that is now known to activate VEGFs and the cascade of events required to stimulate cardiac angiogenesis. Using a regulatory gene is likely more practical than trying to determine which individual growth factor or growth factor combination is best suited for the job.

Simplified Catheter-Based Delivery Options

Even with firm understanding of the merits of individual angiogenic growth factors, a separate question remains: Which DNA delivery system is best suited for cardiovascular angiogenic gene therapy?

Advances have come with a key realization: the facilitation of coronary collateral formation requires a relatively short duration of gene expressiononly a few weeks. Vector systems that meet this requirement include plasmid constructs and adenovirus. So here was the next challenge: determining which of these two approaches was optimal. Plasmids are easy to manufacture and safe but have very low level and short duration of muscle transduction and could be delivered to the heart mainly through direct intramuscular injections. Adenoviral vectors, on the other hand, can be administered via the intravascular route and have been shown to achieve high transfection efficiency in heart muscle cells with transgene expression lasting for two to six weeks. The relatively short duration of growth factor gene expression by the adenovirus serotype 5 (Ad5) vector has proved sufficient for the building of new functional biological structures such as coronary collateral vessels.

Studies have demonstrated that fibroblast growth factor-4 (FGF-4) can promote the growth of existing or new collateral vessels in the heart, when delivered as a gene within an Ad5 vector. The resulting molecular packagenamed Ad5FGF-4is delivered into the heart as a one-time treatment during a standard angiogram-like procedure. The biologic is delivered in front of a balloon that briefly blocks blood flow, allowing the treatment to more easily leave the blood vessel and enter the cardiac muscle. FGF-4 gene expression promotes the development of new collateral vessels and the enlargement of existing collateral vessels in ischemic areas of the heart, to increase blood flow to these oxygen-starved regions.

Effective Clinical Study Design

An additional hindrance to historical progress in cardiovascular gene therapy may have involved study design. The standard endpoint used in most cardiovascular therapeutic angiogenesis studiese.g., exercise tolerance testing (ETT)is based on decades of experience with clinical development of small molecule anti-anginal drugs, and is still considered by regulatory authorities to be a relevant indicator of clinical effectiveness. In general, clinically significant improvements in ETT time resulting from mechanical revascularization (bypass surgery and stents), pharmacologic interventions or gene therapy, represent improved functional capacity for treated patients. ETT is known to be subject to placebo effect, and therefore careful study design, including well-defined patient inclusion criteria (e.g. limited baseline ETT capacity) and controlled testing conditions and criteria are essential for meaningful outcomes.

An attempt to fuse the insights and overcome the roadblocks summarized above are fueling ongoing efforts to improve and advance angiogenic gene therapy. Future studies are likely to elucidate the most promising therapies for cardiovascular angiogenic gene therapy and offer hope to the many patients for whom angina is currently a source of deep concern causing significant negative impact on quality of life.

Christopher J. Reinhard is Chief Executive Officer of Angionetics Inc., a company focused on the late-stage clinical development and commercialization of Generx, an angiogenic gene therapy product candidate designed for medical revascularization for the potential treatment of patients with myocardial ischemia and refractory angina due to advanced coronary artery disease.

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Angiogenic Gene Therapy for the Heart: Overcoming the Roadblocks - Drug Discovery & Development

Pfizer, which scooped up Bamboo Therapeutics last year in its aim to be a major player in gene therapies, is now looking at building a gene therapy production facility in North Carolina where the biotech is based.

Pfizer spokeswoman Kimberly Becker confirmed a report by the Triangle Business Journal that the company has been exploring the area. The newspaper was told by sources that Pfizer has talked to state and local officials about a potential $100 million expansion project. Bamboo is based inChapel Hill.

We recently announced that were moving forward with scoping potential sites in Sanford for our new gene therapy site. This work is still in the preliminary stages and we arent able to share additional detail at this time, Becker said in an email.

The sources told the newspaper thatPfizer also is considering putting it in Massachusetts. The drugmakercurrently is erecting a $200 million biologics and vaccines production facility at its campus in Andover.

But Bamboo already has an 11,000-square foot, fully staffed and operational manufacturing facility in Sanford it acquired last year from the University of North Carolina about the time that Pfizer made an initial investment in the company. Bamboo has produced phase I and II materials using a in the facility using what Pfizer said was superior suspension, cell-based production platform that increases scalability, efficiency and purity.

Pfizer last year bought Bamboo in two-step deal, laying out $193 million to acquire its stock, with a pledge of up to $495 million more in milestones. With gene therapies, genetic material is introduced into a patients body to replace gene mutations that cause disease.

The biotech is working on recombinant adeno-associated virus (rAAV)-based gene therapies for rare diseases. It has a pre-clinical asset for Duchenne Muscular Dystrophy (DMD); and three targeted at the central nervous system, with pre-clinical assets for Friedreichs Ataxia and Canavan disease, and a Phase I asset for Giant Axonal Neuropathy, Pfizer said.

Pfizer first entered the emerging field in 2014 with a deal with Spark Therapeutics in hemophilia. At that time, the company also established a dedicated gene therapy research center in London known as the Genetic Medicines Institute which falls under its Rare Disease Research Unit.

While the field offers the hope of one-time cures by dealing with the genetic root cause of a disease, it offers challenges for insurance coverage and payments. There have been no gene therapies approved yet in the U.S., but Dutch company uniQure developed the firstgene therapy approved in Europe, a treatment thathas been termed the worlds most expensive drug.

Approved in 2012, Glybera is priced at more than $1.2 million. Only one German doctor has been able to win insurance approval, despite the fact the treatment can cure the ultra-rare disease called lipoprotein lipase deficiency. uniQure is now focused on a hemophilia B program, competing with the gene therapy being developed by Spark Therapeutics with Pfizer.uniQure, which has had to eliminatejobs to cut costs, has a $25 million, 55,000-square-foot gene therapy manufacturing facility in Lexington, Massachusetts.

GlaxoSmithKline has also won approval in Europe for Strimvelis, its gene therapy for bubble boy disease. It is offering the one-time treatment at about $665,000, with a money-back guarantee.

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Pfizer looks at building major gene therapy manufacturing facility in ... - FiercePharma

A number of recent headlines imply a case study just published in the New England Journal of Medicine proves that gene therapy has cured sickle cell diseasea genetic disorder that incurs tremendous pain, suffering and diminished life expectancy. Here, we will unpack the significance of the researchers findings.

First, lets address why this news could be so groundbreaking to those afflicted and their loved ones.

Sickle Cell Disease is an inherited condition that causes a mutated hemoglobinthe protein within red blood cells (RBCs) that carries oxygen for delivery to vital tissues. Oxygen feeds our organs so they can stay healthy and perform their respective jobs. This Hemoglobin S (aka Sickle Hemoglobin) polymerizes on deoxygenation and rids the RBCs of their malleability. As a result, these malformed sickled cells are stiff and clump together thereby occluding vessels which in turn prompts organ damage.

Roughly 90,000 Americans have Sickle Cell Disease. (1) The natural course of the illness involves a complex cascade of events intermingled with crises often triggered by infections. Anemia is commonplace (and often profound) given these faulty cells get readily destroyed, over consumed and dont last as long as healthy RBCs. Vasoocclusive Crises result from infarction and ischemiain infants the hands and feet swell, in particular. Basically, adequate blood flow is halted wherever the obstruction takes place. Aggressive pain management and rehydration is essential.

Prophylactic antibiotics are a mainstay in an effort to stave off infection which can routinely catapult patients into a life-threatening crisis. By early childhood, they develop a functional asplenia or ineffective spleen. So, they become especially susceptible to overwhelming infection by encapsulatedbacteriahence, why vaccination for pneumococcus and the like is so important. Sepsis can result. Parvovirus can cause an aplastic crisis.

Strokes. Pulmonary infarcts with subsequent hypoxia. Acute Chest Syndrome. Gallstones. Blood transfusions are frequent. Though the blood supply is well-tested for safety, recurrent transfusion can lead to issues like iron overload, for instance. This too must be treated. The list goes on of the challenges, battles and treatment complexities these patients endure. Because fetal hemoglobin has a higher oxygen carrying capacity, a disease-modifying drug like Hydroxyurea that increases its presence is used.

Allogeneic hematopoietic stem-cell transplantation represents the only cure, but less than 18% of those with severe disease have sibling donors who are a match. (2) This is also not without great risk, though those need to be weighed against how advanced the disease. Due to such limited progress in management of this condition, this team of researchers sought to examine whether therapeutic ex vivo gene transfer into autologous hematopoietic stem cells referred to as gene therapy, may provide a long-term and potentially curative treatment for sickle cell disease. (3)

What does this mean? They took samples from the bone marrow of a patient with severe disease. The cells here provide the origins of our blood components which includes our red blood cells. This is where the problem begins in generating the sickling. A cancer drug, busulfan, was used to condition the body expected adverse effects from this occurred which resolved with standard care (e.g. anemia, low platelets, neutropenia and so on). Using a lentiviral vector, they transferred an anti-sickling gene into the patients stem cells (retrieved from the bone marrow) which get put back into the patient in the hope they will multiply and replace the cells made with the defective gene.

In a study funded in part by Bluebird Bio whose product is LentiGlobin BB305 (the antisickling gene therapy subject of this publication), the team concludes their patient had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease. Furthermore, after fifteen months the antisickling protein remained high at approximately 50% and the patient had no crises or hospitalizations. Before, the patient required regular transfusions. After, all medications were stopped, no pain ones were needed, and the patient returned to full activities at school. (4)

Ongoing research is underway in a U.S. multi center, phase 1/2 clinical study. The intention is to use this gene therapy to treat those with severe sickle cell disease and another condition called beta-thalessemia. So far, in the few patients who have participated, their results seemingly support this work. Clearly, longer term follow-up and larger populations are crucial to understanding the significance of this report. Additionally, stem cell transplantation is no minor feat.

That said, for a disease that disables at such a young age, this option could be quite an extraordinary one if the success persists. ACSHs Senior Fellow in Molecular Biology, Dr. Julianna LeMieux, puts the promise of gene therapy into even greater context for this and other disease entities:"This is an incredibly promising result, even with the obvious caveat that it is only one person. Sickle Cell is a disease that is ripe for genetic advances for a few reasons. First,the gene that is affected is known andcan be replaced by the healthy variant. Also, the cells that are needed to be alteredare easily accessible inthe bone marrow. In many diseases, this is not the case. But, this one success story is incredibly encouraging for the sickle cell community and for moving the field of curing diseases using genetic editing forward."

The team proved their concept. To know if "cure" is in this gene therapy's future, much more data needs to be acquired and study be implemented. Promising with cautious optimism might be the most apt description.

Source(s):

(1) (2) (3) (4) Jean-Antoine Ribeil, M.D., Ph.D. et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 376;848-855. March 2, 2017.

Note(s):

To learn more about "Orphan Diseases" or rare ones that afflict less than 200,000 (but in total impact 25 million Americans) and drug discovery challenges, review: Did Pompe Disease Geta New Champion in President Trump? and Pompe Disease, Newborn Screening and Inborn Errors of Metabolism.

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Did Gene Therapy Cure Sickle Cell Disease? | American Council on ... - American Council on Science and Health

This 2009 colorized microscope image made available by the Sickle Cell Foundation of Georgia via the Centers for Disease Control and Prevention shows a sickle cell, left, and normal red blood cells of a patient with sickle cell anemia.

Janice Haney Carr, AP

A French teen who was given gene therapy for sickle cell disease more than two years ago now has enough properly working red blood cells to dodge the effects of the disorder, researchers report.

The first-in-the-world case is detailed in Thursdays New England Journal of Medicine.

About 90,000 people in the U.S., mostly blacks, have sickle cell, the first disease for which a molecular cause was found. Worldwide, about 275,000 babies are born with it each year.

Vexing questions of race and stigma have shadowed the history of its medical treatment, including a time when blacks who carry the bad gene were urged not to have children, spurring accusations of genocide, Keith Wailoo of Princeton University wrote in a separate article in the journal.

The disease is caused by a single typo in the DNA alphabet of the gene for hemoglobin, the stuff in red blood cells that carries oxygen. When its defective, the cells sickle into a crescent shape, clogging tiny blood vessels and causing bouts of extreme pain and sometimes more serious problems such as strokes and organ damage. It keeps many people from playing sports and enjoying other activities of normal life.

A stem cell transplant from a blood-matched sibling is a potential cure, but in the U.S., fewer than one in five people have a donor like that. Pain crises are treated with blood transfusions and drugs, but theyre a temporary fix. Gene therapy offers hope of a lasting one.

The boy, now 15, was treated at Necker Childrens Hospital in Paris in October 2014. Researchers gave him a gene, taken up by his blood stem cells, to help prevent the sickling. Now, about half of his red blood cells have normal hemoglobin; he has not needed a transfusion since three months after his treatment and is off all medicines.

Its not a cure but it doesnt matter, because the disease is effectively dodged, said Philippe Leboulch, who helped invent the therapy and helped found Bluebird Bio in Cambridge, Massachusetts, the company that treated the boy. The work was supported by a grant from the French governments research agency.

Bluebird has treated at least six others in the U.S. and France. Full results have not been reported, but the gene therapy has not taken hold as well in some of them as it did in the French teen. Researchers think they know why and are adjusting methods to try to do better.

Two other gene therapy studies for sickle cell are underway in the U.S. -- at the University of California, Los Angeles and Cincinnati Childrens Hospital - and another is about to start at Harvard and Boston Childrens Hospital using a little different approach.

This work gives considerable promise for a solution to a very common problem, said Dr. Stuart Orkin, a Boston Childrens Hospital doctor who is an inventor on a patent related to gene editing.

The results are quite good in this patient, he said of the French teen. It shows gene therapy is on the right track.

2017 The Associated Press. All Rights Reserved. This material may not be published, broadcast, rewritten, or redistributed.

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Gene therapy lets a French teen dodge sickle cell disease - CBS News

I agree with Mr Darius Lee (Gene editing will create more divisions in society; March 3) that gene editing should not be used to promote eugenics.

However, gene editing to cure or ameliorate genetic diseases should be viewed as a form of medical advancement, akin to any medical breakthrough in the form of drugs or surgery.

Recently, it was reported that a teenage boy with sickle-cell anaemia was cured of the disease using gene therapy.

Presently, such patients are treated with blood transfusions to clear the blockages caused by abnormal haemoglobin, and have to be on powerful painkillers to manage the painful symptoms. Bone marrow transplants are also used to treat the disease, but finding matching donors can be difficult.

Many other genetic illnesses also exact a grave personal and financial toll on patients and their families.

Besides improving the quality of life for sufferers, gene therapy may also prove to be much less costly in the long term, as sufferers do not need to undergo further treatment.

It can be argued that gene therapy may be accessible only to patients in well-developed medical systems, thus potentially exacerbating the divisions between the "haves" and "have-nots".

But, just as we do not use this as a reason to withhold conventional medical treatment, so we should not condemn those with hereditary illnesses to life-long suffering if gene therapy is available to them.

It behooves society to make such treatments accessible to as many as people possible.

We may also already be"editing" our children's genetic potential with our lifestyle and behavioural choices, such as diet and smoking, as these factors may cause epigenetic modifications.

Studies have found that men who were smokers from an early age had sons who were significantly fatter than average.

Researchers who analysed historical records from a remote part of Sweden found that people whose grandparents had been short of food between the ages of nine and 12 seemed to live longer.

Whether intentionally or not, people have been subjected to varying forms of genetic modifications since time immemorial.

It is only right that gene editing be viewed as just another form of medical treatment to cure illnesses.

Maria Loh Mun Foong (Ms)

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View gene therapy as a medical advancement - The Straits Times

Researchers at Stanford have made mice glow using a new gene therapy technique, showing that the process can work on living animals.

(Courtesy of Linda Cicero).

Named charge-altering releasable transporters (CARTs), the new technique allows researchers to control how much of a desired protein is expressed inside a cell, and how long the gene therapy lasts. It has a variety of applications to many central problems in biology and medicine, including immunology and cancer research.

Previous gene therapy techniques have relied on permanently changing the DNA within a cell. Colin McKinlay, a third-year Ph.D. student in chemistry and co-lead author on the paper, explains that CARTs take advantage of messenger RNA (mRNA) rather than DNA to give researchers greater control over the process.

By introducing mRNA into the cells, you can basically tell those cells to produce any given protein, McKinlay said. Its more of a temporary effect and you have a lot more control over doing that.

However, mRNA molecules are too large to enter the cell on their own. CARTs are able to latch onto the mRNA, cross the cell membrane, release the mRNA into the cell and quickly degrade into small molecules called metabolites naturally recognizable by the cell. After that, the cell takes over, translating the mRNA into the desired proteins.

Its kind of like the cell already has all of the ingredients, McKinlay said. Were just providing the recipe, and the cell then puts all the pieces together.

One possible application of the new gene therapy technique is creating new types of vaccinations. Typical vaccination techniques involve introducing a dead or weakened antigen, bacteria and foreign substances such as viruses into the cell, which the body then uses to create antibodies. CARTs could allow researchers to temporarily introduce specific proteins from the antigens into cells in order to specify targets for the immune system that are less sensitive to antigen mutation.

CARTs also have the potential to be used as a research tool. As transient polycations, CARTs allow proteins to be introduced and manufactured by the cell in controlled quantities and for a controlled amount of time, making them a valuable resource for studying signaling cascades and other biological phenomena.

The team behind CARTs primarily consists ofWender and Waymouth Group researchers, andalso drawson collaborators across Stanford. As the team begins to test the potential applications of CARTs, more researchers are expected to come on board.

In their recent paper on bioluminescent proteins in mice, researchers worked with Christopher Contag, a professor of pediatrics at Stanford, to show that the technique can work in vivo in animal models,bringing the team a step closer to using it in humans.

We couldnt have done it if we were stuck just within the confines of the chemistry department, said Jessica Vargas 16, a formerPh.D. student in the Wender Lab and a co-lead author on the paper. The work in general is a true testament to Stanfords collaborative spirit.

Contact Aulden Foltz at afoltz at stanford.edu.

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Researchers develop controllable gene therapy, make rats glow ... - The Stanford Daily

An experimental gene therapy that turns a patients own blood cells into cancer killers worked in a major study, with more than one-third of very sick lymphoma patients showing no sign of disease six months after a single treatment

In all, 82 percent of patients had their cancer shrink at least by half at some point in the study.

Its sponsor, California-based Kite Pharma, is racing Novartis AG to become the first to win approval of the treatment, called CAR-T cell therapy, in the U.S. It could become the nations first approved gene therapy.

A hopeful sign: the number in complete remission at six months 36 percent is barely changed from partial results released after three months, suggesting this one-time treatment might give lasting benefits for those who do respond well.

The therapy is not without risk. Three of the 101 patients in the study died of causes unrelated to worsening of their cancer, and two of those deaths were deemed due to the treatment.

It was developed at the governments National Cancer Institute and then licensed to Kite. The Leukemia and Lymphoma Society helped sponsor the study.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post: Gene therapy to fight a blood cancer succeeds in major study

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One third of lymphoma patients cancer free after 6 months in CAR-T ... - Genetic Literacy Project

Gene therapy is the use of DNA as a potential therapy to treat a disease.In many disorders, particularly genetic diseases caused by a single genetic defect, gene therapy aims to treat a disease by delivering the correct copy of DNA into a patients cells.The healthy, functional copy of the therapeutic gene then helps the cell function correctly.

In gene therapy, DNA that encodes a therapeutic protein is packaged within a vector, often a naked virus, which is used to transfer the DNA to the inside of cells within the body. Gene therapy can be delivered by a direct injection, either intravenously (IV) or directly into a specific tissue in the body, where it is taken up by individual cells. Once inside cells, the correct DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patients disease and can provide long-term benefit.

Abeona is developing next generation adeno-associated virus (AAV) gene therapies. Viruses such as AAV are utilized because they have evolved a way of encapsulating and delivering one or more genes of the size needed for clinical application, and can be purified in large quantities at high concentration. Unlike AAV vectors found in nature, the AAV vectors used by Abeona have been genetically-modified such that they do not replicate. Although the preclinical studies in animal models of disease demonstrate the promising impact of AAV-mediated gene expression to affected tissues such as the heart, liver and muscle, our programs use a specific virus that is capable of delivering therapeutic DNA across the blood brain barrier and into the central nervous system (CNS), making them attractive for addressing lysosomal storage diseases which have severe CNS manifestations of the disease.

Lysosomal storage diseases (LSD) are a group of rare inborn errors of metabolism resulting from deficiency in normal lysosomal function. These diseases are characterized by progressive accumulation of storage material within the lysosomes of affected cells, ultimately leading to cellular dysfunction. Multiple tissues ranging from musculoskeletal and visceral to tissues of the central nervous system are typically involved in disease pathology.

Since the advent of enzyme replacement therapy (ERT) to manage some LSDs, general clinical outcomes have significantly improved; however, treatment with infused protein is lifelong and continued disease progression is still evident in patients. Thus, viral gene therapy may provide a viable alternative or adjunctive therapy to current management strategies for LSDs.

Our initial programs are focused on LSDs such as Mucopolysaccharidosis (MPS) IIIA and IIIB, also known as Sanfilippo syndromes type A and type B. MPS III is a progressive neuromuscular disease with profound CNS involvement. Our lead product candidates, ABO-101 and ABO-102, have been developed to replace the damaged, malfunctioning enzymes within target cells with the normal, functioning version.

Delivered via a single injection, the drug is only given once.

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Gene Therapy - Abeona Therapeutics

In a world first, a teenager with sickle cell disease achieved complete remission after an experimental gene therapy at Necker Childrens Hospital in Paris, researchers say.

People with sickle-cell disease, a group of inherited blood disorders, have abnormal hemoglobin in their red blood cells, causing blood to clog in the tiny vessels and organs of the body.

After 15 months since treatment, the patient who began therapy at age 13 no longer needs medication, and his blood cells show no further sign of the disease, according to a case report published Thursday in The New England Journal of Medicine.

Since therapy was applied, he hasnt had any pain, any complications. He is free of any transfusions. He plays sports and goes to school, said Dr. Philippe Leboulch, an author of the new research and a professor of medicine at the University of Paris. So we are quite pleased with the results.

This success provides proof of concept for human patients, Leboulch said.

According to Dr. Marina Cavazzana, senior author of the study and head of the biotherapy department at Necker, all the biological tests we perform lead us to think he is cured. Yet, she added, the answer to the question of whether he is truly cured can be provided only by the longer follow-up.

Still, hopes are running high that patients with this very devastating disease can receive this therapy in the next five years, Cavazzana said. This is our hope, and we work very hard to attain it.

A global burden

Worldwide, more than 275,000 infants are born with sickle cell disease each year. In the United States, approximately 100,000 people, most of African ancestry or identifying as black, currently have it. About one in every 365 black children in the US is born with sickle cell disease, for which the life expectancy is now about 40 to 60 years.

Sickle cell disease is one of the most common gene disorders in the world, explained Leboulch. A genetic mutation causes hemoglobin, the main constituent of red blood cells, to distort the shape of the cell, and this causes the blood to aggregate or clog.

This leads to tremendous pain, anemia and also lesions of organs that ultimately result in shortness of life expectancy, Leboulch said. So what we did here was, we tried to inhibit the process of aggregation.

Essentially, researchers extracted bone marrow from the patient, harvested the stem cells and altered the genetic instructions so that they would make normal hemoglobin. Next, they treated the patient with chemotherapy for four days to eliminate his diseased stem cells. Finally, they returned the treated stem cells via an IV into his bloodstream.

At that point, the new cells that were modified outside the body started to make new blood cells, and we hope this will be stable for the life of the patient, Leboulch said.

Before receiving treatment, the teen had terrible pain and needed blood transfusions, which required twice-yearly hospitalizations, Leboulch explained. His many complications included necrosis of the hip, which necessitated hip replacement surgery.

Hope for all patients

Going forward, the plan is to proceed through clinical trials and, if results are promising, make the treatment available to patients. Leboulch and his colleagues are using the same genetic therapy to treat a similar disease called thalassemia, another inherited blood disorder in which patients have less hemoglobin and fewer red blood cells than normal. Severe forms require regular blood transfusions.

Leboulch and his colleagues have global phase 2 and phase 3 trials for the thalassemia treatment underway in France, the US, Australia and Thailand.

For sickle cell disease, a companion trial in the US is underway. I understand that seven (sickle cell) patients have been treated already. Of course, the outcome is much shorter, and we dont have the results just yet, but its coming along, Leboulch said.

To apply this to a baby or a very young child should be at least as effective or more, he said. Doing it with older patients, who have had years of complications, could be more challenging.

Leboulch also noted that gene therapy is easier on patients than procedures requiring outside donors. Previously, hematopoietic stem cell transplant, which replaces a patients bone marrow with that of a donor, has proved an effective cure for some patients.

According to Dr. Alexis Thompson, president-elect of the American Society of Hematology, the majority of sickle cell disease patients do not have a sibling who would be an appropriate match for bone marrow donation.

Gene therapy holds promise because a patient serves as his own donor, and the risks are much reduced since theres no possibility of a mismatch, said Thompson, who was not involved in this research but is an investigator on a related gene therapy study.

I think this is a really very exciting advancement, she said, adding that if the results seen in France can be duplicated, this would provide for a new direction for patients who need a curative option.

According to Dr. Trish Wong of Oregon Health and Science University, the new study is truly amazing work proof of principle that a cure for this chronic, devastating disease is in sight. Wong was not involved in the new research.

Gene therapy offers hope for all patients with sickle cell disease, regardless of whether they have a bone marrow match or not, Wong wrote in an email.

Time is still needed to assess the success of this treatment and the possibility of later side effects, said Wong. But any patient with severe sickle cell disease will tell you that being able to live a life for even a year without medications or fear of pain or hospitalization is substantial.

Finally, Dr. Grace Onimoe of the American Sickle Cell Anemia Association noted that the life expectancy of a patients with sickle cell disease remains decades lower than that of the general population while children throughout the world continue to suffer. Onimoe, who was not involved in the new research, said, As more work continues in the area of gene therapy to enhance safety and reduce potential complications, we remain optimistic of the promise it holds.

Leboulch also feels very hopeful.

Now, we want to be cautious, of course, and we dont want to say that this is the cure for tomorrow or the next day for everybody, he said. At the same time, what weve observed is really convincing, and we just hope that we can move this along to make it available to patients.

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Sickle cell anemia patient 'cured' by gene therapy, doctors say - FOX31 Denver

"The numbers are fantastic," said Dr Fred Locke, a blood cancer expert at Moffitt Cancer Center in Tampa who co-led the study.

"These are heavily treated patients who have no other options."

The treatment, which has been dubbed 'a living drug' by doctors, works by filtering a patient's blood to remove key immune system cells called T-cells, which are then genetically engineered in the lab to recognise cancer cells.

Cancer cells are very good a evading the immune system, but the new therapy essentially cuts the brakes, allowing immune cells to do their job properly.

Martin Ledwick, Cancer Research UKs head cancer information nurse, said: These results are promising and suggest that one day CAR-T cells could become a treatment option for some patients with certain types of lymphoma.

"But, we need to know more about the side effects of the treatment and long term benefits.

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Terminal cancer patients in complete remission after one gene therapy treatment - Telegraph.co.uk

Local company trying to save lives of those fighting rare disease

Monica Robins, WKYC 7:08 PM. EST March 03, 2017

(Photo: Monica Robins, WKYC)

CLEVELAND - Earlier this week, AbeonaTherapeutics, a local biotech company, rang the closing bell on the stock market.

Tuesday was Rare Disease Awareness Day and the company was chosen because of its work. They are giving hope to families fighting diseases that have no treatments or cures.

Inside Abeona Therapeutics, scientists don't have to look far for inspiration. They just have to look on the wall, especially in a little corner of the office meant for visiting kids with a deadly rare disease called Sanfilippo.

"They are usually diagnosed between the ages of two and six and that leads to profound neurological and neuromuscular deficits," according to Abeona Theraputics President and CEO Dr. Timothy Miller. "70 percent don't live to 18."

They're working on gene therapy, using a virus to deliver the correct DNA into each cell with a simple injection.

"We are the only trial in the world right now enrolling patients in this type of disease category," says Dr. Miller.

There are 7,000 rare diseases of which 95% have no treatment or cure. While Sanfilippo is their main focus, the science could one day be a breakthrough.

"Gene therapy is all about delivery and trying to demonstrate that these are actual ways to treat some of these diseases, " explains Dr. Miller. "These will be applicable to many other diseases."

And business is booming. Abeonais looking for more employees to fill these desks. And they just look out their window for possible expansion sites to house a 20,000 square foot manufacturing facility.

Says Dr. Miller, "We're helping people see the possible by bringing jobs to Northeast Ohio, and bringing science into clinical projects. We're hoping to be one of the first gene therapy products in the world."

When Abeona went public in 2015, the company grew 500%. This year, they're looking to expand and have openings for highly skilled people with advanced degrees in biology or chemistry for medical manufacturing positions, clinic trial operations, and program management.

They often recruit from across the country so they're helping Northeast Ohio experience the brain gain.

( 2017 WKYC)

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Possible U | Abeona Therapeutics using gene therapy to see the ... - WKYC-TV

Richard Mulligan

Back in 2010, when Carl Icahn was spooking Henri Termeer and the management of Genzyme, the heavyweight activist investor sent over a list of hand-picked names for new board members that could help shake things up at the company at the time it was grappling with some severe manufacturing problems.

One of those names: Richard Mulligan, a legend in the gene therapy field whose Harvard lab in the 80s included pioneers like James Wilson and Olivier Danos. Mulligan and another of Icahns favorites at the time, Alex Denner, had already vaulted on to the board at Biogen in 2009 to push for changes at the top. And they got it, bringing in George Scangos in a management coup in 2010.

Sanofi wound up buying Genzyme for $20 billion in 2011.

Now, Mulligan, a professor emeritus at Harvard and visiting scientist at MIT, is going to work for Icahn full time as a portfolio manager, with a special focus on biotech.Technically, hes working at Icahn Capital, a subsidiary of Icahn Enterprises $IEP, after joining Denner at Sarissa for the past three years.

Now cue the rampant speculation.

Icahn has sent a shock wave through Bristol-Myers Squibb, arriving to take a piece of equity just as rumors were taking hold that the big biotech damaged by a series of setbacks on Opdivo was ripe for a megamerger. Now that one of Icahns favorite disruptors has come on board full time, could a proxy fight over the board and future direction at Bristol-Myers Squibb be far behind?

I dont know, but who can resist talking about it?

In the meantime, look for Icahn to start making waves in biotech again as Mulligan spearheads new plays in the field.

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Icahn hires on gene therapy legendand big biotech disruptor ... - Endpoints News

"Since therapy was applied, he hasn't had any pain, any complications. He is free of any transfusions. He plays sports and goes to school," said Dr. Philippe Leboulch, an author of the new research and a professor of medicine at the University of Paris. "So we are quite pleased with the results."

This success provides proof of concept for human patients, Leboulch said.

According to Dr. Marina Cavazzana, senior author of the study and head of the biotherapy department at Necker, "all the biological tests we perform lead us to think he is cured." Yet, she added, the answer to the question of whether he is truly cured "can be provided only by the longer follow-up."

Still, hopes are running high that patients with this very devastating disease can receive this therapy "in the next five years," Cavazzana said. "This is our hope, and we work very hard to attain it."

Worldwide, more than 275,000 infants are born with sickle cell disease each year. In the United States, approximately 100,000 people, most of African ancestry or identifying as black, currently have it. About one in every 365 black children in the US is born with sickle cell disease, for which the life expectancy is now about 40 to 60 years.

Sickle cell disease is one of the most common gene disorders in the world, explained Leboulch. A genetic mutation causes hemoglobin, the main constituent of red blood cells, to distort the shape of the cell, and this causes the blood to aggregate or clog.

This leads to "tremendous pain, anemia and also lesions of organs that ultimately result in shortness of life expectancy," Leboulch said. "So what we did here was, we tried to inhibit the process of aggregation."

Essentially, researchers extracted bone marrow from the patient, harvested the stem cells and altered the genetic instructions so that they would make normal hemoglobin. Next, they treated the patient with chemotherapy for four days to eliminate his diseased stem cells. Finally, they returned the treated stem cells via an IV into his bloodstream.

"At that point, the new cells that were modified outside the body started to make new blood cells, and we hope this will be stable for the life of the patient," Leboulch said.

Before receiving treatment, the teen had terrible pain and needed blood transfusions, which required twice-yearly hospitalizations, Leboulch explained. His many complications included necrosis of the hip, which necessitated hip replacement surgery.

Going forward, the plan is to proceed through clinical trials and, if results are promising, make the treatment available to patients. Leboulch and his colleagues are using the same genetic therapy to treat a similar disease called thalassemia, another inherited blood disorder in which patients have less hemoglobin and fewer red blood cells than normal. Severe forms require regular blood transfusions.

Leboulch and his colleagues have global phase 2 and phase 3 trials for the thalassemia treatment underway in France, the US, Australia and Thailand.

For sickle cell disease, a companion trial in the US is underway. "I understand that seven (sickle cell) patients have been treated already. Of course, the outcome is much shorter, and we don't have the results just yet, but it's coming along," Leboulch said.

"To apply this to a baby or a very young child should be at least as effective or more," he said. "Doing it with older patients, who have had years of complications, could be more challenging."

According to Dr. Alexis Thompson, president-elect of the American Society of Hematology, the majority of sickle cell disease patients do not have a sibling who would be an appropriate match for bone marrow donation.

"Gene therapy holds promise because a patient serves as his own donor," and the "risks are much reduced" since there's no possibility of a mismatch, said Thompson, who was not involved in this research but is an investigator on a related gene therapy study.

"I think this is a really very exciting advancement," she said, adding that if the results seen in France can be duplicated, this would provide "for a new direction for patients who need a curative option."

"Gene therapy offers hope for all patients with sickle cell disease, regardless of whether they have a bone marrow match or not," Wong wrote in an email.

"Time is still needed" to assess the success of this treatment and the possibility of later side effects, said Wong. "But any patient with severe sickle cell disease will tell you that being able to live a life for even a year without medications or fear of pain or hospitalization is substantial."

Leboulch also feels very hopeful.

"Now, we want to be cautious, of course, and we don't want to say that this is the cure for tomorrow or the next day for everybody," he said. "At the same time, what we've observed is really convincing, and we just hope that we can move this along to make it available to patients."

Read the rest here:

Sickle cell anemia patient 'cured' by gene therapy, doctors say - CNN

By Margaret Farley Steele

HealthDay Reporter

TUESDAY, Feb. 28, 2017 (HealthDay News) -- An experimental gene therapy for aggressive non-Hodgkin lymphoma beat back more than a third of cancers that seemed untreatable, the therapy's developers report.

Thirty-six percent of over 100 very ill lymphoma patients appeared disease-free six months after a single treatment, according to results released by the treatment's maker, Kite Pharma of Santa Monica, Calif.

These patients had not responded to usual treatments and had no other options, Kite said Tuesday in a news release.

Overall, more than four out of five patients with the blood cancer saw their cancer reduced by more than half for at least part of the study, the company said.

"This seems extraordinary ... extremely encouraging," one cancer specialist, Dr. Roy Herbst, told the Associated Press.

But Herbst, who is chief of medical oncology at Yale Cancer Center in New Haven, Conn., said longer follow-up is needed to see if the benefit continues.

Still, he said, "This certainly is something I would want to have available." Side effects, which had been a concern, seemed manageable in this study, he said.

The therapy -- called CAR-T cell therapy -- enables the patient's own blood cells to kill the cancer cells.

Lymphoma is a general term for cancers that begin in the lymph system. The lymph system is part of the immune system, which helps the body fight disease.

Here's how the treatment works: A patient's blood is filtered so immune cells called T-cells can be altered to contain a cancer-fighting gene. The cells are returned to the patient intravenously, and the cancer-targeting cells then multiply in the patient's body.

The U.S. National Cancer Institute developed the gene approach and licensed it to Kite. Now, Kite and another pharmaceutical giant, Novartis AG, are competing to gain approval of the treatment, according to the AP.

Kite reportedly intends to seek U.S. Food and Drug Administration approval this spring and approval in Europe later this year. It could be the first gene therapy approved in the United States, the news report noted.

Although the therapy appears to benefit a significant number of patients, it is not risk-free. Researchers believe two patients died of treatment-related causes, the AP reported.

Other side effects included anemia or other blood problems that were treated, and neurological problems such as sleepiness, confusion, tremor or difficulty speaking, which typically lasted only a few days, the wire service reported.

Overall, however, the therapy seems safe, according to Dr. Steven Rosenberg, chief of surgery branch at the National Cancer Institute. He was not involved with the study.

"It's a safe treatment, certainly a lot safer than having progressive lymphoma," Rosenberg told the AP. He said he has a patient who was treated this way who is still in remission seven years later.

The cost of such treatment hasn't been reported yet, but immune system therapies tend to be very expensive.

The results are scheduled for presentation at the American Association for Cancer Research conference in April. Until published in a peer-reviewed medical journal, the data and conclusions should be considered preliminary.

WebMD News from HealthDay

SOURCES: Associated Press, Feb. 28, 2017; Kite Pharma Inc., news release, Feb. 28, 2017

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Gene Therapy Shows Promise for Aggressive Lymphoma - WebMD

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In world-first breakthrough, French doctors use gene therapy to treat rare blood disease - RFI

Infants born with a type of the devastating immune disorder SCID, or bubble boy disease, may have the option of a novel gene therapy treatment, thanks to a clinical trial atUCSF Benioff Childrens Hospital San Francisco.

The trial is funded by a five-year, $11.9-million grant from theCalifornia Institute for Regenerative Medicine (CIRM)to test technology developed by St. Jude Childrens Research Hospital that delivers a functional gene into the patients blood-producing stem cells. If successful, the gene therapy could provide an alternative to stem cell transplants using donor cells, which can result in serious infection.

The trial expects to treat up to 15 children over the next five years and is open to patients with X-linked severe combined immunodeficiency disease (X-linked SCID), which affects only males. This is the most common form of SCID, which occurs in 1 in every 60,000 newborns, and is caused by defects in the functioning of lymphocytes the white blood cells that are the advanced fighting forces of the immune system. Babies born with SCID appear normal at birth but become sick from infections, skin rashes and failure to gain weight at 3-to-6 months of age. Without a stem cell transplant, they may die before their first birthday.

What is unique about this trial is that the patients own bone marrow stem cells are collected and corrected with the gene therapy, and the corrected cells are then reinfused into the patient, saidMorton Cowan, M.D., of theUCSF Division of Allergy, Immunology, and Blood and Marrow Transplant, and principal investigator of the trial at UCSF.

In stem cell transplants from a donor other than the patient, up to 20 percent of patients with SCID will develop graft-versus-host disease, in which the donor cells attack the recipients tissues. In addition, there is always a risk of the recipient rejecting the donor cells, Cowan said. Using the patients own stem cells means no rejection and no graft-versus-host disease.

The bone marrow transplant program at UCSF is among the largest SCID transplant centers in North America. UCSF pediatric immunologistJennifer Puck, M.D., is known for pioneering the SCID screening method and for nominating SCID to a federal advisory committee for inclusion in the newborn screening panel. Since the screen became available in California in 2010, UCSF has treated more than 30 infants diagnosed with SCID by newborn screening.

UCSF also played an instrumental role in the St. Jude treatment protocol by including a targeted chemotherapy agent, busulfan, along with the gene therapy, which is expected to optimize immune correction. While previous trials have tested gene therapy for this condition, they did not combine it with chemotherapy and had only partial immune correction. Since a low dose of the medication is used, short- and long-term effects are expected to be minimized.

Three patients already have been treated with this lentiviral gene therapy vector two at St. Jude and one at UCSF. The transduction process, in which genetic material is transferred via vector, currently takes place at St. Jude, which freezes the transduced cells and returns them to UCSF for infusion into the patient. The CIRM funding will enable UCSF to begin doing transductions using the St. Jude vector at theUCSF Pediatric Cell Therapy Laboratory, as well as covering the cost of treating patients in the trial.

We believe this trial will not only help us understand more about how lentiviral gene therapy works, but how the use of low-dose busulfan potentially will be effective in treating other non-malignant diseases like sickle-cell anemia, chronic granulomatous disease, marrow failure syndromes and even some cancers in which the patient is too ill to undergo the more toxic traditional treatments, said Cowan.

It will also give us a better idea of what toxicities may be associated with the use of these new vectors, in particular whether they are indeed safer than the older, gamma-retroviral vectors that were associated with a high risk of leukemia, seen in early gene therapy trials for X-linked SCID and other primary immune deficiencies.

Read the original post:

Gene therapy offers hope for newborns with severe immune disorder - University of California

Every biotech enjoys a good success story, and bluebird bio $BLUE got their writeup in the New England Journal of Medicine. Patient 1204 in bluebirds program for LentiGlobin gene therapy program has had more than 15 months of followup, and his physicians say that the teenager has been free of the painful symptoms of sickle cell disease, able to lead a normal life and stop painful transfusions. Thats all a positive, but bluebirds gene therapy has also proven to be somewhat variable among patients. One success story does not make for a successful therapy, but its still a plus.

Right on the heels of raising 100 million in an IPO, the UKs Arix has struck a deal to partner with Takeda in fostering new biotech startups. The Japanese company has been scaling way back on R&D in the country as Takeda revamps its approach to drug development.

You make hay while the sun shines, and you sell stock right after good data arrives. So its not a big surprise to see Kite line up a sale of 4.75 million shares at $75.00. Its stock $KITE, buoyed by recent 6-month data on its lead CAR-T, is down 5% in morning trading.

The UKs Adaptimmune has opened up its US headquarters in Philadelphias Navy Yard. The cancer company has 92 staffers in the area and plans to boost that figure to 120. Adaptimmune is closely tied to GSK, which also has extensive R&D operations in the area.

News reports for those who discover, develop, and market drugs. Join 13,500+ biopharma pros who read Endpoints News articles by email every day. Free subscription.

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Bluebird's star gene therapy patient still doing well after 15 months-plus; Takeda, Arix partner on biotech startups - Endpoints News

Many rely on blood transfusions

Joe Amon/The Denver Post via Getty

By Andy Coghlan

A TEENAGE boy with an inherited disease that affects millions worldwide seems to have been cured using gene therapy. The treatment appears to have stopped the painful symptoms of sickle cell disease, demonstrating the potential for gene therapy to treat common genetic diseases.

All the blood tests we performed show that the teenager has been cured of sickle cell disease

The idea of gene therapy using strands of DNA to compensate for a persons malfunctioning genes is almost three decades old. However, the approach has so far mostly been used to treat very rare diseases (see Long road to success). In contrast, sickle cell disease affects 100,000 people in the US alone. If the treatment proves successful in larger trials, it could bring gene therapy into widespread use.

It could be a game changer, says Deborah Gill at the University of Oxford. The fact the team has a patient with real clinical benefit, and biological markers to prove it, is a very big deal.

People with sickle cell disease make abnormal versions of haemoglobin, the blood protein that carries oxygen around the body. This can be caused by mutations in the gene that makes a subunit of haemoglobin, called beta-globin. The mutations cause haemoglobin to clump together, distorting red blood cells into a sickle-shape that can get stuck in blood vessels around the body.

People with the disorder are given blood transfusions to clear these painful blockages and prevent new ones. Bone marrow transplants can treat the disease, but matching donors can only be found for around 10 per cent of people with the condition.

Now a team in France seems to have developed a treatment that would work for everyone with the disorder. First, the team took bone marrow stem cells from the boy when he was 13, and gave them extra, mutated versions of the gene that codes for beta-globin. These were designed to make beta-globin that would interfere with the boys faulty proteins, stopping them from clumping together.

The researchers then put these stem cells back into the boys body. After around three months, he began producing large quantities of haemoglobin that behaves normally (New England Journal of Medicine, DOI: 10.1056/NEJMoa1609677). The patient is now 15 years old and free of all previous medication, says Marina Cavazzana at the Necker Childrens Hospital in Paris, who led the team. He has been free of pain from blood vessel blockages, and has given up taking opioid painkillers.

Cavazzana is confident these benefits will last. All the tests we performed on his blood show that hes been cured, but more certainty can only come from long-term follow-up. She says her team has treated seven other patients, who are showing promising progress.

We are all very excited by the work, and this success provides support for this and other genetic strategies targeting this horrible disease, says John Tisdale at the US National Heart, Lung, and Blood Institute in Maryland.

David Williams, at Boston Childrens Hospital in Massachusetts, suggests that the boy may still occasionally experience blockages, because his own original genes are still able to produce faulty haemoglobin. Its important to see what happens over time, and how many other patients see similar benefits.

However, should the gene therapy prove to be effective in larger trials, its expense may limit its use to richer nations. We should be realistic in remembering that there are hundreds of thousands of sickle cell patients in less developed countries, and that the therapy is not easily exportable or adaptable to countries with less well-developed health systems, says Stuart Orkin at Harvard Medical School.

Twenty years ago, gene therapy was touted as a cure for everything from cancer to cystic fibrosis. Now it is finally starting to fulfil its promise.

In 2012, Glybera became the first gene therapy to be approved, for people with a rare disorder that makes them unable to process dietary fat. Last year, the first commercial gene therapy that alters a persons DNA was approved for children with a severe immune disorder. Gene therapies for rare forms of blindness are also showing promise.

But these conditions all affect very small numbers of people. Research into sickle cell disease (see main story), beta thalassaemia, haemophilia and cystic fibrosis mean gene therapy may not be too far from becoming mainstream medicine for the most common genetic diseases.

This article appeared in print under the headline Gene therapy breakthrough

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Gene therapy 'cures' boy of blood disease that affects millions - New Scientist

A 13-year-old boy with sickle cell disease showed no signs of the disease and resumed normal activities 15 months after an infusion of LentiGlobin BB305, according to a study conducted in France and published in The New England Journal of Medicine.

Outcomes in this patient provide further supportive evidence to our previously reported results of patients who underwent a similar ex-vivo gene therapy procedure for beta thalassemia with the same BB305 vector or the previous HPV569 vector, Jean-Antoine Ribeil, MD, PhD, of the department of biotherapy at Necker Childrens Hospital in Paris, and colleagues wrote. In addition to the patient with sickle cell disease described here, under this same clinical protocol, four patients with transfusion-dependent beta thalassemia have received LentiGlobin BB305 [Bluebird Bio] and had no clinically significant complications and no longer require regular transfusions.

Approximately 90,000 people in the United States have sickle cell disease, and more than 275,000 infants worldwide are born with the disease each year.

Granted breakthrough therapy designation by the FDA in 2015, LentiGlobin BB305, is a self-inactivating lentiviral vector that encodes the human HBB variant BetaA-T87Q. This lentiviral vector mediates the addition of an antisickling beta-globin gene into autologous hematopoietic stem cells.

Ribeil and colleagues obtained bone marrow twice from the patient to collect sufficient stem cells for gene transfer and backup. Anemia was the only grade 3 adverse event reported during these procedures.

Researchers then transduced bone marrowenriched CD34positive cells with the LentiGlobin BB305 vector. The mean vector copy numbers for the two batches of transduced cells were 1 and 1.2 copies per cell.

The patient underwent myeloablation with IV busulfan (total busulfan area under the curve, 19,363 mol/minute). After a 2-day washout period, transduced CD34positive cells were infused and red-cell transfusions continued after transplantation until a large proportion of beta-globin chain of adult hemoglobin (HbA)T87Q was detected.

Neutrophil engraftment was achieved on day 38 after transplantation, and platelet engraftment was achieved on day 91 after transplantation. Within 3 months, gene markings in whole blood, CD15 cells, B cells and monocytes had stabilized. Researchers observed more gradual increases in levels of vector-bearing T cells.

HbAT87Q cells increased steadily to 5.5g/dL at month 9 and 5.7 g/dL at month 15 and red-cell transfusions were discontinued on day 88.

The patient was discharged on day 50. By more than 15 months after transplantation, no sickle cell diseaserelated clinical events or hospitalization had occurred, and all medications, including for pain management, were discontinued.

The patient experienced expected grade 3 to grade 4 adverse events of neutropenia, anemia, thrombocytopenia and infection with Staphylococcus epidermidis.

The patient reported full participation in normal academic and physical activities, Ribeil and colleagues wrote.

Researchers noted their finding were consistent with early results reported with 18 other patients with thalassemia who received LentiGlobin BB305 and that longer follow-up is required to confirm the efficacy, durability and safety observed in the study.

In an accompanying perspective, Keith Wailoo, PhD, Townsend Martin professor of history and public affairs at Woodrow Wilson School of Public and International Affairs in Princeton, New Jersey, wrote that findings on the benefits of crizanlizumab (SEG101, Novartis) and gene therapy represent new chapters in treating sickle cell disease.

Patients with sickle cell disease have come a long way from their clinical obscurity 100 years ago, Wailoo wrote. The search for a magic bullet continues, though most clinicians acknowledge that therapies wont cure the disease but merely enhance long-term management. by Chuck Gormley

Disclosure: Bluebird Bio funded the study. Ribeil reports personal fees from Bluebird Bio during the conduct of the study, grant support from AddMedica, and nonfinancial support from Novartis and Vitalaire outside the submitted work. The researchers report no relevant financial disclosures. Wailoo reports no relevant financial disclosures.

See the article here:

Gene therapy product shows early promise in sickle cell disease - Healio

Infants born with a type of the devastating immune disorder SCID, or bubble boy disease, may have the option of a novel gene therapy treatment, thanks to a clinical trial at UCSF Benioff Childrens Hospital San Francisco.

The trial is funded by a five-year, $11.9-million grant from the California Institute for Regenerative Medicine (CIRM) to test technology developed by St. Jude Childrens Research Hospital that delivers a functional gene into the patients blood-producing stem cells. If successful, the gene therapy could provide an alternative to stem cell transplants using donor cells, which can result in serious infection.

The trial expects to treat up to 15 children over the next five years and is open to patients with X-linked severe combined immunodeficiency disease (X-linked SCID), which affects only males. This is the most common form of SCID, which occurs in 1 in every 60,000 newborns, and is caused by defects in the functioning of lymphocytes the white blood cells that are the advanced fighting forces of the immune system. Babies born with SCID appear normal at birth but become sick from infections, skin rashes and failure to gain weight at 3-to-6 months of age. Without a stem cell transplant, they may die before their first birthday.

What is unique about this trial is that the patients own bone marrow stem cells are collected and corrected with the gene therapy, and the corrected cells are then reinfused into the patient, said Morton Cowan, M.D., of the UCSF Division of Allergy, Immunology, and Blood and Marrow Transplant, and principal investigator of the trial at UCSF.

In stem cell transplants from a donor other than the patient, up to 20 percent of patients with SCID will develop graft-versus-host disease, in which the donor cells attack the recipients tissues. In addition, there is always a risk of the recipient rejecting the donor cells, Cowan said. Using the patients own stem cells means no rejection and no graft-versus-host disease.

The bone marrow transplant program at UCSF is among the largest SCID transplant centers in North America. UCSF pediatric immunologist Jennifer Puck, M.D., is known for pioneering the SCID screening method and for nominating SCID to a federal advisory committee for inclusion in the newborn screening panel. Since the screen became available in California in 2010, UCSF has treated more than 30 infants diagnosed with SCID by newborn screening.

UCSF also played an instrumental role in the St. Jude treatment protocol by including a targeted chemotherapy agent, busulfan, along with the gene therapy, which is expected to optimize immune correction. While previous trials have tested gene therapy for this condition, they did not combine it with chemotherapy and had only partial immune correction. Since a low dose of the medication is used, short- and long-term effects are expected to be minimized.

Three patients already have been treated with this lentiviral gene therapy vector two at St. Jude and one at UCSF. The transduction process, in which genetic material is transferred via vector, currently takes place at St. Jude, which freezes the transduced cells and returns them to UCSF for infusion into the patient. The CIRM funding will enable UCSF to begin doing transductions using the St. Jude vector at the UCSF Pediatric Cell Therapy Laboratory, as well as covering the cost of treating patients in the trial.

We believe this trial will not only help us understand more about how lentiviral gene therapy works, but how the use of low-dose busulfan potentially will be effective in treating other non-malignant diseases like sickle-cell anemia, chronic granulomatous disease, marrow failure syndromes and even some cancers in which the patient is too ill to undergo the more toxic traditional treatments, said Cowan.

It will also give us a better idea of what toxicities may be associated with the use of these new vectors, in particular whether they are indeed safer than the older, gamma-retroviral vectors that were associated with a high risk of leukemia, seen in early gene therapy trials for X-linked SCID and other primary immune deficiencies.

See the original post here:

Gene Therapy Offers Hope for Newborns with Severe Immune Disorder - Bioscience Technology