Category Archives: Gene Medicine

By Nuala Moran Staff Writer

BOSTON The triumph of the Massachusetts Institute of Technology Broad Institute and its spinout company Editas Medicine Inc. in the case of CRISPR/Cas9 gene editing patents could impede the development of human therapies based on the technology, according to one of the leading researchers in the field.

George Church, professor of genetics at Harvard Medical School, said, "It definitely is an issue" if Editas maintains exclusivity in applying patents on using CRISPR/Cas9 to edit eukaryote genes. That would limit the freedom to operate of Editas' direct competitors, Intellia Therapeutics Inc. and Crispr Therapeutics AG.

Church added that even if all three companies are equally involved in translation, "that is not enough to handle all the benefits to come out of this. I would love to see more companies," he told AAAS attendees.

Church could be seen as having something of an axe to grind because he published a paper in the same issue of Science as Feng Zhang of the Broad Institute, on using CRISPR/Cas9 in human cells. It is that research of Zhang's on which the disputed patent hangs.

The decision on the high-profile CRISPR/Cas9 patents came a day after the Committee on Human Gene Editing of the National Academies of Sciences and Medicine issued a report concluding that clinical trials involving genome editing in gametes or early embryos could be permitted in the future for serious diseases or disabilities, under stringent oversight. (See BioWorld Today, Feb. 15, 2017, and Feb. 16, 2017.)

Church was one of the contributors to the international summit on gene editing held in Washington in December 2015 that led to the writing of the report. He said the report's proposals amounted to "a change in the red lines we are drawing." When talking about altering the inherited germline and the somatic cells of adults, "the line is now drawn on the seriousness of the disease," he said.

While the red line in germline modification is shifted, the line between using gene editing to cure disease and to enhance human traits becomes softer, Church suggested. For example, gene editing somatic cells to increase muscular strength in patients with muscular dystrophy could tip over into giving subjects greater than average strength.

Similarly, a somatic gene editing to improve cognition as a "cure" for Alzheimer's disease could result in patients having enhanced cognitive abilities.

Such modifications are far from becoming reality, but Church said other traits are more amenable to change. One example would be somatic modification to promote endogenous production of human growth hormone, which could be viewed both as a therapy and as a means of enhancement.

The Committee on Human Gene Editing was convened to try to get ahead of the curve in establishing regulations, before those types of modifications become feasible, as Richard Hynes, professor of cancer at MIT and co-chair of the committee, explained.

While he agreed it is difficult to draw the line between the use of somatic gene editing for treatment of disease and for enhancement, he said he firmly believes enhancement should be banned for now. "We should work out the risk/benefit for therapies first. It will take time to understand the risks. With enhancement, the benefits are debatable, but the risks are the same," Hynes said.

The concern is that, as with stem cell therapies, genetic enhancement through somatic gene editing will be on offer in rogue clinics and in countries where there is limited oversight.

Given that, one of the aims of the committee was to set out core principles that would be broadly influential and could be adopted as the basis for promulgating national laws governing the technology. "The principles are for application around the world, as part of a drive to try and harmonize international regulation," Hynes said.

That is all very well, but as Gary Marchant, of Arizona State University, also a member of the committee, noted, "There is a huge problem of international enforcement." Ways of trying to ensure compliance considered in the report include journals only publishing research that complies with international norms and withholding research grants if the rules are not upheld.

The committee did not consider patenting in its survey of gene editing. However, Marchant suggested refusing licenses could be another mechanism in attempts to ensure appropriate use of the technology worldwide. That "may have more currency at an international level," he said.

Link:
There's a fine red line between cures, enhancements using gene editing tech - BioWorld Online

All inherited diseases and cancers could be cured in the coming decades, according to a leading British expert.

Gene editing techniques that have been developed in recent years could be put to work to effectively end cancer and inherited diseases, according to DrEdze Westra

MrWestra believes that the ability to splice DNA into cells precisely a technology which is on the horizon, but is rejected on moral grounds by many will become super importantover the next 20 years.

It could completely transform the human race, he says so thatpeople are not affected by cancer, failing vision or the diseases of old age.

The bioscientist from the University of Exeter said: There is always a risk with this kind of technology and fears about designer babies and we have started having discussions about that so we can understand the consequences and long-term risks.

I think in the coming decades gene editing will become super important, and I think we will see it being used to cure all inherited diseases, to cure cancers, to restore sight to people by transplanting genes.

I think it will definitely have massive importance.

On Tuesday, two highly influential academic bodies in the US shook up the scientific world with a report that, for the first time, acknowledged the medical potential of editing inherited genes.

The National Academy of Sciences and National Academy of Medicine ruled that gene editing of the human germlineeggs, sperm and embryos should not be seen as a red line in medical research.

Many critics insist that powerful new gene editing techniques should never be used to alter inherited DNA.

They argue that such a move would be the start of a slippery slope leading to designerbabies with selected features such as blue eyes, high intelligence or sporting prowess.

But the two pillars of the American scientific establishment said that with necessary safeguards, future use of germline gene editing to treat or prevent disease and disability was a realistic possibility that deserves serious consideration.

Mr Westra is taking part in a discussion on gene editing and its potential implications for society at the American Association for the Advancement of Science (AAAS) annual meeting in Boston, Massachusetts.

He said gene editing technology not only held out the promise of fixing genetic faults, but could be used to turn cells into miniature factories that churned out therapeutic chemicals or antibodies.

One application was the use of gene drivesthat increase the prevalence of a certain trait in a population.

For instance, gene editing machinery placed inside the cells of large numbers of malaria transmitting mosquitoes could prevent them spreading the organism that carriesthe disease to humans.

It could be a fantastic strategy to deal with some of the worlds biggest problems,said Mr Westra.

In terms of ethics we need to work out what happens if a genetically engineered insect flies out of the window of the lab. Trials into gene drives are already happening in labs for malaria.

The most promising form of gene editing, known as CRISPR/Cas9, was first demonstrated in 2012.

It employs a defence system bacteria useto protect themselves against viruses.

A carefully targeted enzyme is used as chemical scissorsthat cut through specific sections of double stranded DNA. Then the cells own DNA repair machinery can be exploited to insert the pastedgenetic material.

Mr Westra said: Gene editing... is causing a true revolution in science and medicine, because it allows for very precise DNA surgery.

A mutation in a gene that causes disease can now be repaired using CRISPR.

PA

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Gene editing could bring an end to all inherited disease and cancer, expert says - The Independent

Theres a rare disorder that occurs when a gene mutation halts the production of myotubularina protein that facilitates normal muscle function. The disease, called myotubular myopathy (MTM), only affects males, and its ultimately fatal because it causes breathing difficulties.

Dogs get MTM, tooand that spelled opportunity for scientists at the University of Washington Medicine Institute for Stem Cell and Regenerative Medicine. In collaboration with five other academic institutions, they found a way to replace the faulty MTM gene with a functioning gene in dogs with the disease, they reported in the journal Molecular Therapy.

It worked: After a single infusion of genes, muscle strength was restored in the dogs, according to a press release. One year later, the dogs were indistinguishable from healthy animals, they said. "This regenerative technology allowed dogs that otherwise would have perished to complete restoration of normal health," said Dr. Martin K. "Casey" Childers, UW Medicine researcher and physician.

The researchers used a viral vector called adeno-associated virus serotype 8 (rAAV8) to deliver a healthy canine version of the MTM gene in dogs that were 10 weeks old and already showing symptoms. They believe a similar trial could be designed in people.

Gene therapy is under investigation for a wide range of disorders, though much of the progress to date has occurred outside the realm of muscular disorders. BioMarin Pharmaceutical, for example, is in mid-stage trials of a gene therapy treatment for hemophilia A. UniQure is working on several gene therapy products to treat diseases including Huntingtons and congestive heart failure. Its most advanced project, a gene therapy product to treat hemophilia B, received breakthrough designation status from the FDA in January.

One company that has achieved some success with gene therapy in inherited muscle disorders is AveXis, which is gearing up for a pivotal trial of its treatment for spinal muscular atrophy. AveXis won breakthrough therapy designation for its gene product last year, and high hopes for the product have prompted its stock to more than triple since the company went public early last year.

UW Medicine-led team that worked on the canine MTM trial observed that as they increased the dosage of genes, survival rates improved, they reported. They believe the study proves the potential utility of gene therapy in a wide range of diseases that are linked to mutated genes.

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Gene therapy tried in dogs with muscle disease could prove useful for people - FierceBiotech

Work on gene therapy is showing significant progress for restoring muscle strength and prolonging lives in dogs with a previously incurable, inherited neuromuscular disease, according to scientists at the University of Washington (UW) Medicine Institute for Stem Cell and Regenerative Medicine.

The disease arises from a mutation in genes that normally make myotubularin, a protein essential for proper muscle function. Puppies with this naturally occurring mutation exhibit several features of babies with the same defective gene. The rare disorder, called X-linked myotubular myopathy, or XLMTM, affects only males. It causes fatal muscle wasting. Both dogs and boys with the disease typically succumb in early life due to breathing difficulties.

For decades, researchers have struggled to find suitable treatments for genetic muscle diseases like this one. Collaborating research groups in the United States and France found a way to safely replace the disease-causing MTM gene with a healthy gene throughout the entire musculature of affected dogs.

Their most recent findings ("Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs") werepublished online inMolecular Therapy.The paper reports that diseased dogs treated with a single infusion of the corrective therapy were indistinguishable from normal animals 1 year later.

"This regenerative technology allowed dogs that otherwise would have perished to complete restoration of normal health," said Martin K. "Casey" Childers, Ph.D., UW medicine researcher and physician. Dr. Childers is a professor of rehabilitation medicine at the University of Washington School of Medicine and co-director of the Institute for Stem Cell and Regenerative Medicine.

Gene therapy holds the promise to treat many inherited diseases. To date, this approach has not been widely translated into treatment of skeletal muscle disorders.

"We report here a gene therapy dose-finding study in a large animal model of a severe muscle disease where a single treatment resulted in dramatic rescue," said Dr. Childers. The findings demonstrate potential application across a wide range of diseases and broadly translate to human studies. The data supports the development of gene therapy clinical trials for myotubular myopathy, the researchers concluded.

The study was conducted in collaboration with Harvard University, Medical College of Wisconsin, Virginia Tech, INSERM, and Genethon.

Excerpt from:
Rare Muscle Disease Treated Successfully with Gene Therapy - Genetic Engineering & Biotechnology News

February 16, 2017 Credit: UNIGE

When a child is conceived, he or she receives DNA from both parents. The child's own genome thus consists of a maternal and a paternal genome. However, some genesabout 100 out of the 20,000 encoded genes are exclusively expressed either from the maternal or from the paternal genome, with the other copy of the gene remaining silent. We know that these imprinted genes are more likely to lead to serious genetic diseases, such as PraderWilli or Angelman syndrome. Researchers at the University of Geneva (UNIGE), Switzerland, have devised a new technique, based on a combination of biology and bioinformatics, to quickly and accurately detect the imprinted genes expressed in each of the cell types that constitute the human organs. This major breakthrough will improve our understanding and diagnosis of genetic diseases. The study can be read in full in the American Journal of Human Genetics.

The research team, led by Professor Stylianos Antonarakis from the Department of Genetic Medicine and Development in the Faculty of Medicine at UNIGE, focused on genomic imprinting. This is a set of genes exclusively expressed from the genetic code inherited either from the father (the paternal allele) or from the mother (maternal allele). Why is there so much interest in the identification of the imprinted genes? Because if a deleterious mutation affects the functional allele, it cannot be compensated by the expression of the second silent allele, likely causing a serious genetic disease. The goal, therefore, is to determine the imprinted genes in all cell types of human body tissues that are liable to cause these kind of diseases.

Until recently, millions of cells were analysed together without distinction. "We have now developed a new technique with a better resolution, known as Human Single-Cell Allele-Specific Gene Expression," explains Christelle Borel, UNIGE researcher. "The process can be used to simultaneously examine the expression of the two alleles, paternal and maternal, of all known genes in each individual cell. The method is fast and can be carried out on thousands of single cells with the utmost precision using next-generation sequencing technology." The heterogeneity of each tissue of the body is thus analysed in detail while searching for imprinted genes in disease-relevant tissue. The individual's genome is sequenced, as is the genome of both parents, in order to identify the parental origin of the alleles transcribed in the person's single cell.

Each cell is unique

Federico Santoni, first author of the study and researcher at UNIGE and HUG (Geneva University Hospitals) further explains, "We establish the profile of the allelic expression for thousands of genes in each single cell. We then process this data with a novel computational and statistical framework to identify the specific signature of each imprinted gene, enabling us to accurately record them." This new technique redefines the landscape of imprinted genes by examining all cell types, and can be applied to all tissues affected by diseases, such as cardiac and brain tissue. Moreover, the scientists have discovered novel imprinted genes and demonstrated that some were restricted to certain tissues or cell types.

This technique focuses on the specific characteristics of each individual by treating each cell as a single entity. This concept, called Single-cell Genomics, is part of an emerging field that is assuming an all-important role at UNIGE, which sees it as the future of medicine that will be personalised rather than generalised. Thanks to the technique pioneered by UNIGE researchers, it will be possible to identify new disease causing genes and to adapt a specific and targeted treatment for individual patients.

Explore further: Expanding the brain: Research identifies more than 40 new imprinted genes

More information: Federico A. Santoni et al. Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression, The American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.01.028

It's among the cornerstones of biology: All mammals inherit two copies one from their mother, the other from their fatherof every gene, in part to act as a backstop against genetic problems. If a gene is damaged or ...

A poor diet during pregnancy can cause biological changes that last throughout life, according to research from Imperial College London.

Every cell in the body has two genomes, one from the mother and one from the father. Until now, researchers have lacked the tools to examinein a single cell the exact readout from each genome to make RNA. Using a new ...

Researchers at Karolinska Institutet and Ludwig Institute for Cancer Research have characterized how and to what degree our cells utilize the gene copies inherited from our mother and father differently. At a basic level ...

The development of the cerebral cortex played a major role in the evolution of mankind. Scientists are now studying the emergence of its cellular microstructure with high resolution methods. Neuroscientists at the University ...

Personalized medicine, which involves tailoring health care to each person's unique genetic makeup, has the potential to transform how we diagnose, prevent and treat disease. After all, no two people are alike. Mapping a ...

Work on gene therapy is showing significant progress for restoring muscle strength and prolonging lives in dogs with a previously incurable, inherited neuromuscular disease. UW Medicine Institute for Stem Cell and Regenerative ...

A genomic study of baldness identified more than 200 genetic regions involved in this common but potentially embarrassing condition. These genetic variants could be used to predict a man's chance of severe hair loss. The ...

Purdue University and Indiana University School of Medicine scientists were able to force an epigenetic reaction that turns on and off a gene known to determine the fate of the neural stem cells, a finding that could lead ...

Just before Rare Disease Day 2017, a study from the Monell Center and collaborating institutions provides new insight into the causes of trimethylaminura (TMAU), a genetically-transmitted metabolic disorder that leads to ...

Monash University and Danish researchers have discovered a gene in worms that could help break the cycle of overeating and under-exercising that can lead to obesity.

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Stepping up the hunt for genetic diseases - Medical Xpress

Scientists should be allowed to altera persons DNA in ways that will be passed on to future generations, but only to prevent serious and strongly heritable diseases, according to a new report from the National Academy of Sciences and the National Academy of Medicine.

However, tinkering with these genes in orderto enhance or alter traits such as strength, intelligence or beauty should remain off-limits, the report authors concluded.

Changing theso-called germline effectively, editing humanitys future by altering genes in human reproductive cells is illegal in the United States. It has largely been considered ethically off-limits here as well, at least whilebioethicists and scientists pondered the unforeseen effects and unexamined moral dilemmas of using new gene-editing technologies.

However, scientists have moved forward aggressively to explore the feasibility of altering disease genes in other adult human cells with a revolutionarytechnique known asCRISPR-Cas9. It is widely believed that gene editing of this sort could treat patients with metabolic disorders, certain cancers, anda range of otherdiseases that arise from genetic mutationswithout altering the germline.

Last year, Chinese scientists launched a trial that uses CRISPR-Cas9 in a treatment for lung cancer. While the trials outcome is awaited with high anticipation, scientists outside of China have expressed concern that ethical reservations in the United States and Europe will put themat a disadvantage.

CRISPR-Cas9 makesgene editing more straightforward, more precise and far more widespread. As such, the National Academies report acknowledgesthat changingheritable DNA ineggs, sperm and early embryosis fast becoming a realistic possibility that deserves serious consideration.

The 22-memberpanel of scientists and bioethicists who produced the report completed a comprehensive review of the issues raised by that prospect.

Clinical trials involving germline editing should onlybe pursuedto treat diseases that cannot be improvedwith reasonable alternatives, the committee said. In addition, they added,scientists should convincingly demonstratethey are targeting a gene that eithercauses or strongly predisposes a carrier to a serious disease or condition, and that they have weighed the likely risks and benefits of altering that gene.

These clinical trials should be conducted under public scrutiny that takes into account issues ofsocietal fairness, personal dignityand scientific integrity, the panel said.

Finally, scientists should conduct long-term follow-up studies to discern how gene editing affects subsequent generations.Public debate and discussion about the technologyshould continue, the panel added.

Genome editing research is very much an international endeavor, and all nations should ensure that any potential clinical applications reflect societal values and be subject to appropriate oversight and regulation, saidMIT cancer researcher Richard O.Hynes, who co-chaired the panel with University of Wisconsin-Madison bioethicist R. Alta Charo. These overarching principles and the responsibilities that flow from them should be reflected in each nations scientific community and regulatory processes.

Dr. J. Patrick Whelan, an immunologist and bioethicist who was not on the panel, said the grouphas asked the compelling questions, sparkinga conversation that must keep up with a rapid pace of scientific discovery in this field. He called the reportsrelease a fantastic development.

What theyre saying is, lets start the conversation, maintain ethical structures along the way, and hopefully do this the right way, said Whelan, who serves on the advisory board of USCs Institute for Advanced Catholic Studies.

The international panel included members from the U.S., China, France, Israel andItaly.Their report was underwritten in part by the Department of Defenses Advanced Research Projects Agency and the U.S. Food and Drug Administration.

melissa.healy@latimes.com

Follow me on Twitter @LATMelissaHealy and "like" Los Angeles Times Science & Health on Facebook.

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To prevent serious medical conditions, scientists should be able to edit people's DNA, panel says - Los Angeles Times