Category Archives: Gene Medicine

March 8, 2017

Today, in vitro fertilization provides a way for couples to avoid passing potentially disease-causing genes to their offspring. A couple will undergo genetic screening. Tests will determine whether their unborn children are at risk. If embryos created through IVF show signs of such a genetic mutation, they can be discarded.

Flash forward a few years, and, instead of being discarded, those embryos can be repaired with new gene editing technologies. And those repairs will affect not only those children, but all their descendants

This is definitely new territory, said Pasquale Patrizio, M.D., director of the Yale Fertility Center and Fertility Preservation Program. We are at the verge of a huge revolution in the way disease is treated.

We are at the verge of a huge revolution in the way disease is treated.

In a move that seems likely to help clear the path for the use of gene editing in the clinical setting, on February 14 the Committee on Human Gene Editing, formed by the National Academy of Medicine and the National Academy of Sciences, recommended that research into human gene editing should go forward under strict ethical and safety guidelines. Among their concerns were ensuring that the technology be used to treat only serious diseases for which there is no other remedy, that there be broad oversight, and that there be equal access to the treatment. These guidelines provide a framework for discussion of technology that has been described as an ethical minefield and for which there is no government support in the United States.

A main impetus for the committees work appears to be the discovery and widespread use of CRISPR-Cas9, a defense that bacteria use against viral infection. Scientists including former Yale faculty member Jennifer Doudna, Ph.D., now at the University of California, Berkeley, and Emmanuelle Charpentier, Ph.D., of the Max Planck Institute for Infection Biology in Berlin, discerned that the CRISPR enzyme could be harnessed to make precision cuts and repairs to genes. Faster, easier, and cheaper than previous gene editing technologies, CRISPR was declared the breakthrough of the year in 2015 by Science magazine, and has become a basic and ubiquitous laboratory research tool. The committees guidelines, said scientists, physicians, and ethicists at Yale, could pave the way for thoughtful and safe use of this and other human gene editing technologies. In addition to CRISPR, the committee described three commonly used gene editing techniques; zinc finger nucleases, meganucleases, and transcription activator-like effector nucleases.

Patrizio, professor of obstetrics, gynecology, and reproductive sciences, said the guidelines are on the mark, especially because they call for editing only in circumstances where the diseases or disabilities are serious and where there are not alternative treatments. He and others cited such diseases as cystic fibrosis, sickle cell anemia, and thalassemia as targets for gene editing. Because they are caused by mutations in a single gene, repairing that one gene could prevent disease.

Peter Glazer, M.D. 87, Ph.D. 87, HS 91, FW 91, chair and the Robert E. Hunter Professor of Therapeutic Radiology and professor of genetics, said, The field will benefit from guidelines that are thoughtfully developed. This was a step in the right direction.

The panel recommended that gene editing techniques should be limited to deal with genes proven to cause or predispose to specific diseases. It should be used to convert mutated genes to versions that are already prevalent in the population. The panel also called for stringent oversight of the process and for a prohibition against use of the technology for enhancements, rather than to treat disease. As physicians, we understand what serious diseases are. Many of them are very well known and well characterized on a genetic level, Glazer said. The slippery slope is where people start thinking about modifications in situations where people dont have a serious disorder or disease.

Mark Mercurio, M.D., professor of pediatrics (neonatology), and director of the Program for Biomedical Ethics, echoed that concern. While he concurs with the panels recommendations, he urged a clear definition of disease prevention and treatment. At some point we are not treating, but enhancing. This in turn, he said, conjures up the nations own medical ethical history, which includes eugenics policies in the early 20th century that were later adopted in Nazi Germany. This has the potential to help a great many people, and is a great advance. But we need to be cognizant of the history of eugenics in the United States and elsewhere, and need to be very thoughtful in how we use this technology going forward, he said.

The new technology, he said, can lead to uncharted ethical waters. Pediatric ethics are more difficult, Mercurio said. It is one thing to decide for yourselfis this a risk Im willing to takeand another thing to decide for a child. It is another thing still further, which we have never had to consider, to decide for future generations.

Myron Genel, M.D., emeritus professor of pediatrics and senior research scientist, served on Connecticuts stem cell commission and four years on the Health and Human Services Secretary's Advisory Committee on Human Research Protections. He believes that Connecticuts guidelines on stem cell research provide a framework for addressing the issues associated with human gene editing. There is a whole regulatory process that has been evolved governing the therapeutic use of stem cells, he said. There are mechanisms that have been put in place for effective local oversight and national oversight for stem cell research.

Although CRISPR has been the subject of a bitter patent dispute between Doudna and Charpentier and The Broad Institute in Cambridge, Mass., a recent decision by the U.S. Patent Trial and Appeal Board in favor of Broad is unlikely to affect research at Yale and other institutions. Although Broad, an institute of Harvard and the Massachusetts Institute of Technology, can now claim the patent, universities do not typically enforce patent rights against other universities over research uses.

At Yale, scientists and physicians noted that gene editing is years away from human trials, and that risks remain. The issue now, said Glazer, is How do we do it safely? It is never going to be risk-free. Many medical therapies have side effects and we balance the risks and benefits. Despite its effectiveness, CRISPR is also known for whats called off-target risk, imprecise cutting and splicing of genes that could lead to unforeseen side effects that persist in future generations. CRISPR is extremely potent in editing the gene it is targeting, Glazer said. But it is still somewhat promiscuous and will cut other places. It could damage a gene you dont want damaged.

Glazer has been working with a gene editing technology called triple helix that hijacks DNAs own repair mechanisms to fix gene mutations. Triple helix, as its name suggests, adds a third strand to the double helix of DNA. That third layer, a peptide nucleic acid, binds to DNA and provokes a natural repair process that copies a strand of DNA into a target gene. Unlike CRISPR and other editing techniques, it does not use nucleases that cut DNA. This just recruits a process that is natural. Then you give the cell this piece of DNA, this template that has a new sequence, Glazer said, adding that triple helix is more precise than CRISPR and leads to fewer off-target effects, but is a more complex technology that requires advanced synthetic chemistry.

Along with several scientists across Yale, Glazer is studying triple helix as a potential treatment for cystic fibrosis, HIV/AIDS, spherocytosis, and thalassemia.

Adele Ricciardi, a student in her sixth year of the M.D./Ph.D. program, is working with Glazer and other faculty on use of triple helix to make DNA repairs in utero. She also supports the panels decision, but believes that more public discussion is needed to allay fears of misuse of the technology. In a recent presentation to her lab mates, she noted that surveys show widespread public concern about such biomedical advances. One study found that most of those surveyed felt it should be illegal to change the genes of unborn babies, even to prevent disease.

There is, I believe, a misconception of what we are using gene editing for, Ricciardi said. We are using it to edit disease-causing mutations, not to improve the intelligence of our species or get favorable characteristics in babies. We can improve quality of life in kids with severe genetic disorders.

This article was submitted by John Dent Curtis on March 8, 2017.

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Gene editing opens the door to a revolution in treating and preventing disease - Yale News

Boston Business Journal

Intellia R&D head says new gene-editing data shows path to human trials Boston Business Journal Cambridge-based Intellia Therapeutics had the biggest IPO of any local biotech in 2016, but shares of the company have lagged in recent months, and it has often been overshadowed by its gene-editing rival in Kendall Square, Editas Medicine. and more »

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Intellia R&D head says new gene-editing data shows path to human trials - Boston Business Journal

NEW YORK (GenomeWeb) Before the National Institutes of Health can begin to genetically test participants within its precision medicine initiative, it will have to figure out what results to return, how to minimize reporting false positives, and how to provide counseling to help them navigate the often uncertain and evolving evidence on genetic information.

And the project will have to figure out how to do all this on an unprecedented scale, for a million participants that the All of Us Research Program hopes to enroll over the next four years.

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Precision Medicine Project Mulls How to Return Genetic Test Results to 1 Million Participants - GenomeWeb

Optogenetics From Wikipedia, the free encyclopedia Optogenetics (from Greek optiks], meaning seen, visible) is a biological technique which involves the use of light to control cells in living tissue, typically neurons, that have been genetically modified to express light-sensitive ion channels. It is a neuromodulation method employed in neuroscience that uses a combination of techniques from optics and genetics to control and monitor the activities of individual neurons in living tissueeven within freely-moving animalsand to precisely measure the effects of those manipulations in real-time.[1] The key reagents used in optogenetics Read more

GeneQuine develops drugs that are based on gene therapy. The concept of gene therapy is to introduce genetic material into the patients own cells in the body. The cells produce then a therapeutic protein according to the template that the introduced genetic material (DNA) provides

GeneQuine is focused on the development of gene therapy agents for the treatment of osteoarthritis. Osteoarthritis is a degenerative joint disorder characterized by cartilage loss and inflammation. Patients affected by osteoarthritis experience joint pain as well as swelling and stiffness of the joints leading to Read more

Genome Editing with CRISPR-Cas9

Heres a short list of some common diseases that might be curable or preventable with gene editing:

Autism Breast cancer Colon cancer Hemophilia Huntingtons disease Marfan, Parkinsons Prostate cancer Retinitis pigmentosa Sickle cell Skin cancer Tay-Sachs Wilson Duchenne muscular dystrophy Crohns Color blindness Cystic fibrosis Down syndrome Polycystic kidney Turner syndrome.

There are hundreds of other more rare genetic disorders. Read more

Gene therapy is a well-suited approach for the treatment of SMA due to the monogenic nature of the diseasemeaning its caused by the deletion of or mutations in a single gene. AVXS-101 is our clinical-stage, proprietary gene therapy candidate of a one-time, intravenous treatment for SMA Type 1designed to prevent further muscle degeneration caused by SMA through:

Delivery of a fully functional human SMN gene into target motor neuron cells Production of sufficient levels of SMN protein required to improve motor neuron function Rapid onset of effect in addition to Read more

Advantagene Inc. Bluebird Bio Genethon Human Stem Cells Institute Oxford BioMedica Plc Sanofi Shanghai Sunway Biotech Co. Ltd. Sibiono GeneTech Co. Ltd. Spark Therapeutics, LLC UniQure N.V. Vical Inc. ViroMed Co. Ltd. dba VM BioPharma Read more

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RNAi.technology - RNAi Medicine, RNAi Developments, Gene ...

TUESDAY, March 7, 2017 (HealthDay News) -- A drug used to treat Alzheimer's disease should not be prescribed to people with milder mental impairment without first giving them a genetic test, a new study urges.

The drug is donepezil (brand name: Aricept).

Donepezil could speed mental decline in someone with mild cognitive impairment who has a specific genetic variation, according to Sophie Sokolow, an associate professor at the UCLA School of Nursing.

She and her colleagues found that patients with the K-variant of the butyrylcholinesterase (BChE) gene who took donepezil deteriorated faster than those who took a placebo.

Donepezil is approved in the United States to treat Alzheimer's disease but not mild cognitive impairment -- the stage between normal age-related decline and dementia. However, doctors often prescribe it "off-label" for patients with mild cognitive impairment, the study authors said.

For this study, the researchers examined data from a U.S. government-funded study published in 2005 that assessed donepezil as a possible treatment for mild cognitive impairment.

The findings reinforce the importance of physicians discussing the possible benefits and risks of donepezil with their patients, the researchers said in a university news release.

The study was published recently in the Journal of Alzheimer's Disease. Funding was provide by the U.S. National Institute on Aging.

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Study: Gene Test Needed Before Using Alzheimer's Drug 'Off-Label' - Montana Standard

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 Science and Health