Category Archives: Gene Medicine

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

March 8, 2017 White fat stores energy, while brown fat dissipates energy by producing heat, mediated by uncoupling protein 1, or UCP1. Credit: Ray Soccio, MD, PhD, Perelman School of Medicine, University of Pennsylvania

By comparing two strains of miceone that becomes obese and diabetic on a high-fat diet and another resistant to a high-fat regimenresearchers from the Perelman School of Medicine at the University of Pennsylvania identified genome-wide changes caused by a high-fat diet.

The a team, led by Raymond Soccio, MD, PhD, an assistant professor of Medicine, and Mitchell Lazar, MD, PhD, director the Institute for Diabetes, Obesity, and Metabolism, published their findings online in the Journal of Clinical Investigation (JCI), in addition to an Author's Take video.

"We focused on the epigenome, the part of the genome that doesn't code for proteins but governs gene expression," Lazar said.

Their research suggests that people who may be genetically susceptible to obesity and type 2 diabetes due to low levels of a protein that helps cells burn fat, may benefit from treatments that ultimately increase the fat-burning molecule.

The team looked at the interplay of genes and environment in two types of white fat tissue, subcutaneous fat (under the skin) versus visceral fat around abdominal organs. The latter correlates strongly with metabolic disease. This visceral fat shows major gene expression changes in diet-induced obesity. The JCI study confirmed this relationshipand importantlyextended these findings to show that the epigenome in visceral fat also changes on a high fat diet.

Diet-induced epigenomic changes in fat cells occur at histones - proteins that package and order DNA in the nucleus, which influences gene expression - across the genome. There were also changes in the binding to DNA of an essential fat cell protein, a transcription factor called PPARgamma.

The team next treated obese mice with the drug rosiglitazone, which targets PPARgamma in fat to treat diabetes in people. "While the drug-treated obese mice were more insulin sensitive, we were surprised to see that the drug had little effect on gene expression in visceral fat," Soccio said. "This led us to look at subcutaneous fat and we discovered that this depot is much more responsive to the drug."

"These results are clinically relevant and indicate that the 'bad' metabolic effects of obesity occur in visceral fat, while the 'good' effects of rosiglitazone and other drugs like it occur in subcutaneous fat," Lazar said.

In particular, the drug-induced changes they found in subcutaneous fat reflected the phenomenon of browning, in which white fat takes on characteristics of brown fat, typically in response to cold exposure or certain hormones and drugs.

White fat stores energy, while brown fat dissipates energy by producing heat, mediated by uncoupling protein 1, or UCP1. The most interesting discovery of the study, say the authors, involves UCP1.

They showed that rosiglitazone, as expected, increases Ucp1 expression in both obesity-prone and obesity-resistant strains of mice. However, in subcutaneous fat of the obesity-resistant mice, Ucp1 expression was high even in the absence of the drug. "But the real surprise came when we looked at the offspring of obesity-resistant and obesity-prone parents, which have one of each parent's version of the Ucp1 gene," Soccio said.

Strikingly, they found that the obesity-prone mouse strain's version of the Ucp1 gene has lower expression and less PPARgamma binding than the obesity-resistant version. This imbalance shows that the obesity-prone mouse strain's Ucp1 is genetically defective, since it is less active than the other strain's version, even when both are present in the same cell nucleus.

In their final experiments, the team asked what happens when browning and Ucp1 expression are activated using rosiglitazone or exposure to cold, both environmental factors. They found that in both cases, total Ucp1 expression goes up as expected, but the obesity-prone strain's defective version of Ucp1 now reaches equal levels to the obesity-resistant strain's version.

"Importantly, we were only changing the mouse's environment with a drug or temperature, not the actual DNA sequence of the Ucp1 gene," Lazar said. "We propose that this result indicates epigenomic rescue of Ucp1 expression in subcutaneous fat cells."

The team is following up the mouse studies using human fat biopsies to figure out the exact DNA sequence differences responsible for variable Ucp1 expression, both in mice and in humans.

The relevance of this study extends even beyond UCP1 and obesity. "Many gene variants are thought to exert their effects by ultimately altering gene expression levels, and this study shows that a genetic predisposition to altered gene expression can be identified and then overcome with treatment," Lazar said. "This is the dream of precision medicine, and hopefully our study is a step in this direction."

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Study parses influence of genes and environment in metabolic disease - Medical Xpress

-- Dalcetrapib Studied in Genetically Distinct Patients with Acute Coronary Syndrome --

LONDON and MONTREAL, March 7, 2017 /PRNewswire/ --DalCor Pharmaceuticals today announced it is ahead of the enrollment schedule with the randomization of over 1,000 patients of the expected 5,000 patients planned for the Phase 3 "dal-GenE" clinical trial, a cardiovascular outcomes study of dalcetrapib in patients with acute coronary syndrome (ACS) and the AA genotype in the ADCY9 gene. Patients have been recruited at 642 hospitals in 30 countries, including the U.S., and on six continents.

The worldwide clinical trial is led by the Montreal Health Innovations Coordinating Center (MHICC), the Lead Academic Research Organization (ARO) and Medpace a leading Clinical Research Organization (CRO).

Approximately 1 in 5 of the general population harbor the AA genotype.

Quotes

Jean-Claude Tardif, C.M., M.D., director of the Research Center at the Montreal Heart Institute and professor of medicine at the Universit de Montral, and Principal Investigator for dal-GenE said, "We are pleased and gratified that recruitment goals are ahead of schedule. This is a testament to the need for precision medicine in this critically important sector of medicine; the DalCor approach is the first for cardiovascular medicine. Furthermore, it clearly shows the interest in the study and the necessity for a new therapeutic alternative for patients."

Marc Pfeffer, Dzau Professor of Medicine, Harvard Medical School, Senior Physician, Brigham and Women's Hospital, Consultant to the dal-GenE executive committeeand chair of the prior dal-Outcomes Safety Committee, said, "This impressive recruitment despite requiring a specific genotypereflects well on bothDalCor's experiencedinternational leadership team as well as the motivation of sites and their patients to be part of this major trial addressing a genetically targeted "precision medicine" approach. When completed, dal-GenE will be the first major test of pharmacogenetically profiling patients to improve prognosis following a recent myocardial infarction."

Donald Black, M.D., chief medical officer of DalCor, said, "This significant milestone is the result of the efforts of multiple parties collaborating around the world. Our clinical team, in partnership with a strong network of investigators and other groups, such as ANMCO in Italy, GLCC in New Zealand and ECLA in Argentina and Chile, have been able to work together and significantly improve the study's recruitment rate. It is the hard work of the dedicated team that has enabled the surprisingly quick physician response that has enabled DalCor to reach this important milestone in the short time since initiation.

We believe this compound has a unique profile and possesses a unique combination of safety and efficacy attributes for targeted patients which has the potential to greatly improve outcomes for patients worldwide.

There is much ahead, but DalCor is committed to completing this high-quality trial to obtain a reliable answer to this important question. For now, we look forward to continuing our clinical work in the dal-GenE trial, where we expect to demonstrate a significant reduction in heart attacks, strokes and cardiovascular deaths with the addition of dalcetrapib to the standard of care including statins in patients with ACS and the appropriate genetic profile."

About DalcetrapibDalcetrapib is the first precision medicine in the cardiovascular space to have reached full-scale development with this Phase III clinical study. Over 17,000 patients have participated in dalcetrapib clinical trials to date.

In 2012, investigators at the Montreal Heart Institute led by Professors Jean-Claude Tardif and Marie-Pierre Dub found a significant association between the effects of dalcetrapib in altering CV events and the polymorphism at the rs1967309 location in the adenylate cyclase type 9 (ADCY9) gene. Patients with the AA genotype had a 39% reduction in CV events when treated with dalcetrapib compared to placebo, while GG patients had a 27% increase and AG patients had a neutral effect. This analysis was conducted in 5749 patients. A prospective analysis of the dal-Plaque 2 study data has also demonstrated reduced atherosclerosis in the AA population when treated with dalcetrapib, but an increase in atherosclerosis in the GG population.

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About the dal-GenE StudyThe double-blind, randomized, placebo-controlled, multicenter Phase 3 clinical trial will enroll 5,000 patients recently hospitalized with ACS and who express the AA genotype at variant rs1967309 in the ADCY9 gene, determined by an investigational companion diagnostic test developed by Roche Molecular Systems (RMS).

The primary endpoint of the study is the time to first occurrence of any component of the composite of cardiovascular death, myocardial infarction (heart attack) and stroke. The trial will be conducted at 880 sites in 33 countries.

About DalCor PharmaceuticalsDalCor is developing precision treatments by genetically targeting patients that will derive clinical benefits. By integrating clinical and genetic insights, DalCor intends to deliver superior clinical cardiovascular outcomes. The company's first development program, dalcetrapib, is intended to reduce cardiovascular events in a specific genetic subset of patients.

DalCor secured a worldwide exclusive license for dalcetrapib together with rights to the genetic marker for use with dalcetrapib and is sponsoring the dal-GenE study, which is planned to include 5,000 patients to prospectively confirm the results of the pharmacogenomic analysis in the dal-Outcomes study in a patient population with the AA genotype at the rs1967309 location in the ADCY9 gene.

DalCor Pharmaceuticals has offices in Montreal, San Mateo, Calif., Zug, Switzerland and Stockport, U.K. For more information, visit http://www.dalcorpharma.com.

About the Montreal Heart InstituteFounded in 1954 by Dr. Paul David, the Montreal Heart Institute constantly aims for the highest standards of excellence in the cardiovascular field through its leadership in clinical and basic research, ultra-specialized care, professional training and prevention. It is part of the broad network of health excellence made up of Universit de Montral and its affiliated institutions. The Montreal Heart Institute ranks as the No. 1 research hospital in Canada for research intensity and research funds per researcher, according to Research Infosource. For more information, please visit http://www.icm-mhi.org.

DalCor Contacts:

CorporateDalCor PharmaceuticalsDonald M. Black, MD (609) 613-6637 dblack@dalcorpharma.com

MediaRusso PartnersAlexander Fudukidis (646) 942-5632 alex.fudukidis@russopartnersllc.com

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/dalcors-phase-3-cardiovascular-trial-dal-gene-exceeds-targeted-enrollment-schedule-300418898.html

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DalCor's Phase 3 Cardiovascular Trial, dal-GenE, Exceeds Targeted Enrollment Schedule - Yahoo Finance

the Irish News

New genetic research provides hope for families with rare diseases the Irish News The centre, spearheaded by consultant in genetic medicine Dr Shane McKee, have been involved in the design and operation of the UK-wide Deciphering Developmental Disorders (DDD) Study since 2011. The DDD Study involves scientists sequencing the ...

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New genetic research provides hope for families with rare diseases - the Irish News

Researchers in the Department of Molecular and Human Genetics at Baylor College of Medicine have identified a previously unimplicated gene behind a particular form of chondrodysplasia, a skeletal dysplasia that affects cartilage formation and causes disproportionate short stature and premature osteoarthritis. The study appears in the Journal of Clinical Investigation.

Stemming from research being performed at Baylor and its genetics department as part of a systematic search for genetic causes of skeletal dysplasias, the project set out to identify the genetic driver behind Shohat type spondyloepimetaphyseal dysplasia (SEMD). It was led by Dr. Brendan Lee, professor and chair of molecular and human genetics at Baylor, and a team of researchers including project leader Adetutu Egunsola, a genetics graduate student.

SEMD is a rare type of skeletal dysplasia that impacts the development of cartilage and results in a form of dwarfism, characterized by a particular pattern of joint abnormalities, scoliosis and defects of the long bones.

Through combined whole exome sequencing and studies in zebrafish and mice, Lee and his team were able to identify a completely new gene associated with this skeletal dysplasia, DDRGK1, and discovered how it functions in cartilage. In zebrafish, for example, a DDRGK1 deficiency disrupts craniofacial cartilage development and causes a decrease in levels of the protein SOX9.

Not only did we discover the requirement of DDRGK1 in maintaining cartilage, but we also found that it to be a regulator of SOX9, which is the master transcription factor that controls cartilage formation the human skeleton, said Lee, who also holds the Robert and Janice McNair Endowed Chair in molecular and human genetics. If you do not have the SOX9 protein, you do not have cartilage it drives the production of cartilage in growth plates and joint cartilage all over the body.

The relationship between DDRGK1 and SOX9 reveals a novel mechanism that regulates chondrogenesis, or cartilage maintenance and formation, by controlling SOX9 ubiquitination, a process that controls the degradation of proteins like SOX9. Loss of the function of DDRGK1 causes this cartilage dysplasia in part via accelerated destruction of SOX9.

Studying this skeletal dysplasia resulted in the biological insight about this gene that had never been implicated in any disease condition related to the skeleton, Lee said. The future is to find out whether DDRGK1s function more globally controls ubiquitination in general and to determine how this process could be targeted for treating patients with dwarfism.

Other contributors to this work include Richard Gibbs, Adetutu T. Egunsola, Yangjin Bae, Ming-Ming Jiang, David S. Liu, Yuqing Chen-Evenson, Terry Bertin, Shan Chen and James T. Lu with Baylor, Nurit Magal with Rabin Medical Center, Annick Raas-Rothschild with Sheba-Tel Hashomer Medical Center, Eric C. Swindell with the University of Texas Graduate School of Biomedical Sciences, Lisette Nevarez and Daniel H. Cohn with the University of California, Philippe M. Campeau with the University of Montreal and Mordechai Shohat with the Sackler School of Medicine at Tel Aviv University.

This research was supported by the BCM Intellectual and Developmental Disabilities Research Center and a Program Project grant from the Eunice and Kennedy Shiver National Institute of Child Health and Human Development, the BCM Advanced Technology Cores with funding from the NIH, the Rolanette and Berdon Lawrence Bone Disease Program of Texas, the BCM Center for Skeletal Medicine and Biology and Tel Aviv University.

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Genetic driver behind rare skeletal dysplasia condition found - Baylor College of Medicine News (press release)

Tuesday, March 07, 2017 5:23 p.m. CST

By Will Boggs MD

(Reuters Health) - Genetic changes in the cells lining the inside of the nose might someday help doctors diagnose lung cancer, a recent study suggests.

The idea that you don't have to sample the disease tissue but can diagnose presence of disease using relatively accessible cells that are far from the tumor . . . is a paradigm that can impact many cancers, Dr. Avrum Spira from Boston University School of Medicine, a member of the study team, told Reuters Health by email.

The layer of cells that covers the surfaces of the body and lines the cavities is known as the epithelium. Researchers found that distinctive changes in gene activity in the nasal epithelium of lung cancer patients closely parallel the changes seen in lung epithelium and can distinguish between benign lung disease and cancer.

"I think the most interesting finding was the genomic changes in the nasal epithelium of lung cancer patients mirror so closely those found in the lower airway, Spira said.

The researchers thought the nose would be a reasonable surrogate for the field of injury in the bronchial airway, he added, but the surprisingly strong concordance between the nose and lower airway gave them the encouragement to develop a nasal biomarker for lung cancer detection.

Pulmonary nodules represent a growing diagnostic dilemma in the U.S. as we have started to screen for lung cancer, Spira said. A nasal swab that is highly sensitive for lung cancer in this setting would enable physicians to avoid unnecessary invasive biopsies in nodule patients who are unlikely to have lung cancer.

Past research has found that gene expression profiles from normal bronchial epithelial cells can distinguish smokers and former smokers with lung cancer from individuals with benign lung disease, and that nasal and bronchial epithelium respond similarly to tobacco smoke.

Spiras team sought to determine whether cancer-associated gene expression in the nasal epithelium might be useful for detecting lung cancer in current and former smokers.

They identified 535 genes that had different activity patterns in the nasal epithelium of patients with lung cancer versus those with benign disease.

Cancer-associated gene changes correlated significantly between nasal epithelium and bronchial epithelium samples, and the genes that were more active in nasal epithelium of patients with lung cancer were among the genes whose activity was most increased in bronchial epithelium of patients with cancer.

When researchers compared models doctors might use to determine the likelihood of lung cancer, nasal gene activity was more accurate than clinical risk factors alone for diagnosing lung cancer, according to the Journal of the National Cancer Institute report.

The combination of clinical factors and gene activity score accurately predicted cancer 91 percent of the time, compared to 79 percent for the model based on risk factors. The combined model also had 85 percent accuracy differentiating lung cancer from benign disease, compared to 73 percent.

One of the big-picture messages for physicians is that molecular tests like this one are emerging as part of precision medicine approaches for early cancer detection, Spira said.

SOURCE: http://bit.ly/2mdEWcl Journal of the National Cancer Institute, online February 27, 2017.

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Gene activity in the nose may signal lung cancer - KFGO

From brain implants to a map of human cells, the Massachusetts Institute of Technology is out with its annual list of 10 breakthrough technologies. And although its peppered with cool stuff like face-detecting tech that can authorize payments and 360-degree selfies, three healthcare breakthroughs made this years list.

Scientists are making remarkable progress at using brain implants to restore the freedom of movement that spinal cord injuries take away, according to the report.

In recent years, lab animals and a few people have controlled computer cursors or robotic arms with their thoughts, thanks to a brain implant wired to machines, the authors write. Now researchers are taking a significant next step toward reversing paralysis once and for all. They are wirelessly connecting the brain-reading technology directly to electrical stimulators on the body so that peoples thoughts can again move their limbs.

Researchers have been chasing the dream of gene therapy for decades. Until recently it had produced more disappointments than successes. But now, crucial puzzles have been solved and gene therapies are on the verge of curing devastating genetic disorders.

Fixing rare diseases, impressive in its own right, could be just the start, according to the article.

RELATED:Hype surrounds precision medicine, but significant challenges remain

The first comprehensive map of human cells should reveal, for the first time, what human bodies are made of, providing scientists with a sophisticated new model of biology that could speed the search for drugs, according to the article.

We will see some things that we expect, things we know to exist, but Im sure there will be completely novel things, Mike Stubbington, head of the cell atlas team at the Sanger Institute in the U.K., tells the publication. I think there will be surprises.

RELATED:C-suiters: Keep an eye on these technologies in 2017

Practical quantum computers, reinforcement learning and the botnet of things also made this years list. Connected devices in the home, an item of interest to healthcare organizations, are particularly vulnerable to hackers, the article notes. And that makes it easier than ever to build huge botnets that take down much more than one site at a time.

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3 breakthroughs that will change medicine - FierceHealthcare

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

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Akcea Therapeutics, a wholly owned subsidiary of Ionis Pharmaceuticals, Inc. (NASDAQ: IONS), today announced that the pivotal Phase 3 APPROACH study of volanesorsen met its primary endpoint of reducing triglyceride levels in patients with familial chylomicronemia syndrome (FCS).

APPROACH is a randomized, double-blind, placebo-controlled, 52-week Phase 3 study in 66 patients with FCS, a rare disease affecting approximately 3,000 to 5,000 patients worldwide. The average incoming triglyceride level of patients in the study was 2,209 mg/dL. Patients treated with volanesorsen experienced robust reductions in triglycerides and related benefits as follows:

"We are excited about the strong profile of volanesorsen in not only robustly reducing triglycerides, but also providing additional important patient benefits. FCS is a life-threatening, rare disease with multiple severe daily and chronic manifestations. We believe the efficacy and safety data from volanesorsen studies demonstrate a favorable risk-benefit profile for patients with FCS," said Paula Soteropoulos, president and chief executive officer, Akcea Therapeutics.

The APPROACH study will support the regulatory submission for FCS of volanesorsen. Additional data from the study will be presented at an upcoming medical meeting.

"People with FCS have inherited mutations that inhibit the activity of lipoprotein lipase, the enzyme required to break down triglycerides carried by chylomicrons. The results from this study provide encouraging data about triglyceride reduction in patients with FCS treated with volanesorsen, and are consistent with data from other clinical trials with the drug. Since there are currently very few effective treatment options for FCS patients, I am encouraged that, if approved, volanesorsen could offer FCS patients an option to achieve the therapeutic benefit they need," said Daniel Gaudet, M.D. Ph.D., head of the Clinical Lipidology and Rare Lipid Disorders Unit, Community Gene Medicine Center, Department of Medicine, Universit de Montreal.

The APPROACH results were consistent with findings from both the Phase 3 COMPASS study as well as the Phase 2 program for volanesorsen. In the COMPASS study, the five FCS patients treated for three months with volanesorsen experienced a 73% average decrease in triglycerides, which represented a mean absolute reduction of 1,511 mg/dL. In the Phase 2 program, which was the subject of two separate publications in the New England Journal of Medicine, the three FCS patients profiled in one publication had an average triglyceride reduction after three months of treatment with volanesorsen of 69% or a mean absolute reduction of 1,298 mg/dL.

"The success of APPROACH represents an important milestone towards our first regulatory submissions for volanesorsen in the U.S., Europe and Canada in 2017," said Dr. Louis O'Dea, chief medical officer, Akcea Therapeutics. "We seek to bring this new treatment as expeditiously as possible to FCS patients who have a high unmet need with potentially life-threatening consequences."

In the study, there were no treatment-related liver adverse events, including no increases in liver fat. There were no treatment-related renal adverse events. The most common adverse event in the volanesorsen-treated group of patients was injection site reactions (ISRs), which were mostly mild. Five volanesorsen-treated patients discontinued due to ISRs. Declines in platelet counts associated with decreases in triglycerides were observed in many patients. These were generally well managed with dose adjustment. Five volanesorsen-treated patients discontinued due to declines in platelets. No patients discontinued in the last six months of the study after platelet monitoring was fully implemented. In the volanesorsen Phase 3 program, there were infrequent serious platelet events (grade 4 thrombocytopenia) in three volanesorsen-treated patients, which resolved without incident following cessation of dosing. In the entire volanesorsen clinical program 232 individuals have been treated with volanesorsen, including 66 FCS patients, some for more than two years.

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March 6, 2017

A sweeping international effort is connecting the dots between genes in our fat cells and our risk for obesity and cardiometabolic diseases such as heart disease and type 2 diabetes. The researchers have identified approximately 90 genes found in fat that could play important roles in such diseases - and could be targeted to develop new treatments or cures.

Unlike many genetics studies, the huge project looked at how genes' activity actually manifests in human patients - in this case, 770 Finnish men. The results will help doctors and scientists better understand how normal gene variations can affect individuals' health and risk for disease.

"There are a lot of regions in our genomes that are associated with increased risk for, let's say, type 2 diabetes. But we don't always understand what's happening in these regions," said Mete Civelek, PhD, of the University of Virginia School of Medicine. "This study actually addresses some of those questions."

Gene Effects on Health

The men used in the study have had their health histories, body composition, blood work and other wellness factors recorded in astoundingly complete detail - Civelek called them "one of the very few extremely well characterized populations in the world." The precise documentation allowed the researchers to draw conclusions about the effects of gene variations that naturally occur in subcutaneous fat. "Type 2 diabetes, coronary artery disease and obesity are multifactorial and complex diseases," Civelek said. "Genetic factors do not work in isolation - they work in a holistic way, so I think that these kind of studies that we are publishing are key to understanding what's happening in human populations."

That understanding could translate into better treatments for cardiometabolic diseases that pose a tremendous public health threat. Heart disease, for example, is the No. 1 killer in the United States. "Maybe by looking at these other markers we will be able to predict someone's risk much better, so that, for example, they can modify their diet or lifestyle even before type 2 diabetes develops," Civelek said. "Or let's say type 2 diabetes has already developed. We might be able to target some of these novel genes as a potential cure."

DNA in 3D

The project helps advance a more sophisticated - and three-dimensional - view of our DNA. Typically, people think of DNA as long, neat strands, laid out like a stretched string. But in reality, the strands are clumped together inside cells like spaghetti. Genes that appear far away from each other when viewed linearly actually may be quite close when DNA is balled up inside the cell. That physical proximity affects what they do.

"For a lot of cases, what we found was that these different genomic regions actually affect gene expression in a far-away locus, not necessarily the immediate neighborhood," he said. "That's because the DNA is compacted and there's a three-dimensional structure. [Genes] can actually come together in three-dimensional space and can affect each other."

That can have big implications for understanding what genes are doing. "We're saying that it may be the gene that we thought was causing a phenomenon is not," Civelek said. "There may actually be another gene at work that is a little bit farther away."

Civelek, of UVA's Department of Biomedical Engineering, is already hard at work on a follow-up to the project, examining a potential "master switch" that may be regulating the activity of many different genes associated with obesity, HDL (or "good") cholesterol level and risk for type 2 diabetes.

Findings Published

The effort included researchers from UVA; the University of North Carolina at Chapel Hill; the University of California, Los Angeles; Bristol-Myers Squibb; the University of Eastern Finland; the University of Michigan, Ann Arbor; the National Institutes of Health's National Human Genome Research Institute; and King's College London. Their findings have been published in the American Journal of Human Genetics.

Explore further: Gene variants associated with body shape increase risk of heart disease, type 2 diabetes

More information: Mete Civelek et al, Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.01.027

Journal reference: American Journal of Human Genetics

Provided by: University of Virginia Health System

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