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Category Archives: Genetic Medicine

Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder – Newswise

Newswise PHILADELPHIAScientists in the Perelman School of Medicine at the University of Pennsylvania have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCM which affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failure is one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In the study, published this week in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cells but not two other cell types studied leading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, said study co-senior author Rajan Jain, MD, an assistant professor of Cardiovascular Medicine and Cell and Developmental Biology at the Perelman School of Medicine.

Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause, said study co-senior author Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine and Genetics, and Director of the Genetic and Epigenetic Origins of Disease Program at Penn Medicine.

Inherited LMNA mutations have long puzzled researchers. The LMNA gene encodes proteins that form a lacy structure on the inner wall of the cell nucleus, where chromosomes full of coiled DNA are housed. This lacy structure, known as the nuclear lamina, touches some parts of the genome, and these lamina-genome interactions help regulate gene activity, for example in the process of cell division. The puzzle is that the nuclear lamina is found in most cell types, yet the disruption of this important and near-ubiquitous cellular component by LMNA mutations causes only a handful of relatively specific clinical disorders, including a form of DCM, two forms of muscular dystrophy, and a form of progeria a syndrome that resembles rapid aging.

To better understand how LMNA mutations can cause DCM, Jain, Musunuru, and their colleagues took cells from a healthy human donor, and used the CRISPR gene-editing technique to create known DCM-causing LMNA mutations in each cell. They then used stem cell methods to turn these cells into heart muscle cells cardiomyocytes and, for comparison, liver and fat cells. Their goal was to discover what was happening in the mutation-containing cardiomyocytes that wasnt happening in the other cell types.

The researchers found that in the LMNA-mutant cardiomyocytes but hardly at all in the other two cell types the nuclear lamina had an altered appearance and did not connect to the genome in the usual way. This disruption of lamina-genome interactions led to a failure of normal gene regulation: many genes that should be switched off in heart muscle cells were active. The researchers examined cells taken from DCM patients with LMNA mutations and found similar abnormalities in gene activity.

A distinctive pattern of gene activity essentially defines what biologists call the identity of a cell. Thus the DCM-causing LMNA mutations had begun to alter the identity of cardiomyocytes, giving them features of other cell types.

The LMNA-mutant cardiomyocytes also had another defect seen in patients with LMNA-linked DCM: the heart muscle cells had lost much of the mechanical elasticity that normally allows them to contract and stretch as needed. The same deficiency was not seen in the LMNA-mutant liver and fat cells.

Research is ongoing to understand whether changes in elasticity in the heart cells with LMNA mutations occurs prior to changes in genome organization, or whether the genome interactions at the lamina help ensure proper elasticity. Their experiments did suggest an explanation for the differences between the lamina-genome connections being badly disrupted in LMNA-mutant cardiomyocytes but not so much in LMNA-mutant liver and fat cells: Every cell type uses a distinct pattern of chemical marks on its genome, called epigenetic marks, to program its patterns of gene activity, and this pattern in cardiomyocytes apparently results in lamina-genome interactions that are especially vulnerable to disruption in the presence of certain LMNA mutations.

The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome, Jain said. This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.

Other co-authors of the study were co-first authors Parisha Shah and Wenjian Lv; and Joshua Rhoades, Andrey Poleshko, Deepti Abbey, Matthew Caporizzo, Ricardo Linares-Saldana, Julie Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam Stanton, Kenneth Bedi, Michael Morley, Thomas Cappola, Anjali Owens, Kenneth Margulies, David Frank, Joseph Wu, Daniel Rader, Wenli Yang, and Benjamin Prosser.

Funding was provided by the Burroughs Wellcome Career Award for Medical Scientists, Gilead Research Scholars Award, Pennsylvania Department of Health, American Heart Association/Allen Initiative, the National Institutes of Health (DP2 HL147123, R35 HL145203, R01 HL149891, F31 HL147416, NSF15-48571, R01 GM137425), the Penn Institute of Regenerative Medicine, and the Winkelman Family Fund for Cardiac Innovation.

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Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise

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Breast Cancer Gene Mutations Found in 30% of All Women – Medscape

New findings of breast cancer gene mutations in women who have no family history of the disease offer a new way of estimating risk and may change the way in which these women are advised on risk management.

The findings come from two large studies, both published on January 20 in The New England Journal of Medicine.

The two articles are "extraordinary" for broadening and validating the genomic panel to help screen women at risk for breast cancer in the future, commented Eric Topol, MD, professor of molecular medicine, Scripps Research, La Jolla, California, and Medscape editor-in-chief.

"Traditionally, genetic testing of inherited breast cancer genes has focused on women at high risk who have a strong family history of breast cancer or those who were diagnosed at an early age, such as under 45 years," commented the lead investigator of one of studies, Fergus Couch, PhD, pathologist at the Mayo Clinic, Rochester, Minnesota.

"[Although] the risk of developing breast cancer is generally lower for women without a family history of the disease...when we looked at all women, we found that 30% of breast cancer mutations occurred in women who are not high-risk," he said.

In both studies, mutations or variants in eight genes BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were found to be significantly associated with breast cancer risk.

However, the distribution of mutations among women with breast cancer differed from the distribution among unaffected women, notes Steven Narod, MD, from the Women's College Research Institute, Toronto, Ontario, Canada, in an accompanying editorial.

"What this means to clinicians, now that we are expanding the use of gene-panel testing to include unaffected women with a moderate risk of breast cancer in the family history, is that our time will increasingly be spent counseling women with CHEK2 and ATM mutations," he writes. Currently these two are "clumped in with 'other genes'.... [M]ost of the pretest discussion is currently focused on the implications of finding a BRCA1 or BRCA2 mutation."

The new findings may lead to new risk management strategies, he suggests. "Most breast cancers that occur in women with a mutation in ATM or CHEK2 are estrogen receptor positive, so these women may be candidates for anti-estrogen therapies such as tamoxifen, raloxifene, or aromatase inhibitors," he writes.

Narod observes that for now, the management of most women with either mutation will consist of screening alone, starting with MRI at age 40 years.

The medical community is not ready yet to expand genetic screening to the general population, cautions Walton Taylor, MD, past president of the American Society of Breast Surgeons (ASBrS).

The ASBrS currently recommends that all patients with breast cancer as well as those at high risk for breast cancer be offered genetic testing. "All women at risk should be tested, and all patients with pathogenic variants need to be managed appropriately it saves lives," Taylor emphasized.

However, "unaffected people with no family history do not need genetic testing at this time," he told Medscape Medical News.

As to what physicians might do to better manage patients with mutations that predispose to breast cancer, Taylor said, "It's surprisingly easy."

Every genetic testing company provides genetic counselors to guide patients through next steps, Taylor pointed out, and most cancer patients have nurse navigators who make sure patients get tested and followed appropriately.

Members of the ASBrS follow the National Comprehensive Cancer Network guidelines when they identify carriers of a pathogenic variant. Taylor says these are very useful guidelines for virtually all mutations identified thus far.

"This research is not necessarily new, but it is confirmatory for what we are doing, and that helps us make sure we are going down the right pathway," Taylor said. "It confirms that what we think is right is right and that matters," he reaffirmed.

The study led by Mayo's Couch was carried out by the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. It involved analyzing data from 17 epidemiology studies that focused on women in the general population who develop breast cancer. For the studies, which were conducted in the United States, pathogenic variants in 28 cancer-predisposition genes were sequenced from 32,247 women with breast cancer (case patients) and 32,544 unaffected women (control persons).

In the overall CARRIERS analysis, the prevalence of pathogenic variants in 12 clinically actionable genes was 5.03% among case patients and 1.63% among control persons. The prevalence was similar in non-Hispanic White women, non-Hispanic Black women, and Hispanic case patients, as well as control persons, they add. The prevalence of pathogenic variants among Asian American case patients was lower, at only 1.64%, they note.

Among patients who had breast cancer, the most common pathogenic variants included BRCA2, which occurred in 1.29% of case patients, followed by CHEK2, at a prevalence of 1.08%, and BRCA1, at a prevalence of 0.85%.

Mutations in BRCA1 increased the risk for breast cancer more than 7.5-fold; mutations in BRCA2 increased that risk more than fivefold, the investigators state.

Mutations in PALB2 increased the risk of breast cancer approximately fourfold, they add.

Prevalence rates for both BRCA1 and BRCA2 among breast cancer patients declined rapidly after the age of 40. The decline in other variants, including ATM, CHEK2, and PALB2, was limited with increasing age.

Indeed, mutations in all five of these genes were associated with a lifetime absolute risk for breast cancer greater than 20% by the age of 85 among non-Hispanic Whites.

Pathogenic variants in BRCA1 or BRCA2 yielded a lifetime risk for breast cancer of approximately 50%. Mutations in PALB2 yielded a lifetime breast cancer risk of approximately 32%.

The risk of having a mutation in specific genes varied depending on the type of breast cancer. For example, mutations in BARD1, RAD51C, and RAD51d increased the risk for estrogen receptor (ER)negative breast cancer as well as triple-negative breast cancer, the authors note, whereas mutations in ATM, CDH1, and CHEK2 increased the risk for ER-positive breast cancer.

"These refined estimates of the prevalences of pathogenic variants among women with breast cancer in the overall population, as opposed to selected high-risk patients, may inform ongoing discussions regarding testing in patients with breast cancer," the BCAC authors observe.

"The risks of breast cancer associated with pathogenic variants in the genes evaluated in the population-based CARRIERS analysis also provide important information for risk assessment and counselling of women with breast cancer who do not meet high-risk selection criteria," they suggest.

The second study was conducted by the Breast Cancer Association Consortium (BCAC) under lead author Leila Dorling, PhD, University of Cambridge, United Kingdom. This group sequenced 34 susceptibility genes from 60,466 women with breast cancer and 53,461 unaffected control persons.

"Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) were associated with a significant risk of breast cancer overall (P < .0001)," the BCAC members report. "For these genes, odds ratios ranged from 2.10 to 10.57," they add.

The association between overall breast cancer risk and mutations in seven other genes was more modest, conferring approximately twice the risk for breast cancer overall, although that risk was threefold higher for the TP53 mutation.

For the 12 genes the consortium singled out as being associated with either a significant or a more modest risk for breast cancer, the effect size did not vary significantly between European and Asian women, the authors note. Again, the risk forER-positive breast cancer was over two times greater for those who had either the ATM or the CHEK2 mutation. Having mutations in BARD1, BRCA1, BRCA1, PALB2, RAD51C, and RAD51D conferred a higher risk for ER-negative disease than for ER-positive disease.

There was also an association between rare missense variants in six genes CHEK2, ATM, TP53, BRCA1, CDH1, and RECQL and overall breast cancer risk, with the clearest evidence being for CHEK2.

"The absolute risk estimates place protein-truncating variants in BRCA1, BRCA2, and PALB2 in the high-risk category and place protein-truncating variants in ATM, BARD1, CHEK2, RAD51CC, and RAD51D in the moderate-risk category," Dorling and colleagues reaffirm.

"These results may guide screening as well as prevention with risk-reducing surgery or medication, in accordance with national guidelines," the authors suggest.

The CARRIERS study was supported by the National Institutes of Health. The study by Dorling and colleagues was supported by the European Union Horizon 2020 research and innovation programs, among others. Narod has disclosed no relevant financial relationships.

New Eng J Med. Published online January 20, 2021. Couch et al, Abstract; BCAC study, Full text; Editorial

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Breast Cancer Gene Mutations Found in 30% of All Women - Medscape

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Neurophth Therapeutics Further Expands Ocular Gene Therapy Expertise with Appointment of Qiutang Li, Ph.D., as Chief Scientific Officer – PRNewswire

Dr. Li has over 30 years of experience in basic and applied biomedical research. She joins Neurophth from the University of Louisville School of Medicine, where she was a professor in the department of Ophthalmology and Visual Sciences for over 14 years. Her research focuses on the role of Hippo/YAP1 signaling pathway on different stages of ocular development, NF-kB/IKK2 inhibition of neovascularization, and gene discovery screening for eye diseases using mouse models.

Throughout her career, Dr. Li has contributed to more than 45 publications in journals including Investigative Ophthalmology & Visual Science (IOVS), Proceedings of the National Academy of Sciences of the United States of America(PNAS), Nature Review Immunology, and Science. She is currently the editorial board member of Scientific Reportsand Source Journal of Ophthalmology. Dr. Li holds a Ph.D. in cell biology from the Washington University in St. Louis and obtained both her Bachelor's and Master of Science degrees in Genetics from Beijing University.

"We are thrilled to have Dr. Li on our team, bringing over 3 decades of her diverse experience in basic and applied biomedical research," said Bin Li, M.D., Ph.D., Founder and Chairman of the Board of Neurophth. "Given her prior experience at Baylor College of Medicine mentored by Dr. Savio Woo, an internationally recognized expert in molecular human genetics and gene therapy, and Dr. Mark Kay, a leading researcher in the fields of AAV gene therapy and the current Head of Division of Human Gene Therapy at the Stanford University School of Medicine, Dr. Li has extensive knowledge in gene therapy for hepatic deficiencies, ocular diseases, and viral vector reconstruction."

"We are excited to have Qiutang join and expand our exceptional research and development team. She brings a wealth of experience in gene therapies for ocular diseases to Neurophth," said Alvin Luk, Ph.D., M.B.A., C.C.R.A., Chief Executive Officer at Neurophth. "Her deep understanding of viral vector design and animal models in the inhibition of neovascularization for ocular diseases, such as age-related macular degeneration and diabetic retinopathy, further bolsters our ability to deliver on our growing pipeline of clinical programs and platform capabilities."

"It has been captivating to watch the scale, scope, and speed with which Neurophth has successfully transformed itself into an innovative and diversified gene therapy company," said Dr. Li. "I look forward to being a part of Neurophth team as the company executes the next stage of its growth strategy and expands its pipeline of gene therapy candidates focused on ocular and non-ocular diseases, building a brighter future for patients worldwide."

About Neurophth

Neurophth is China's first gene therapy company in ophthalmic diseases.Headquartered in Wuhan with subsidiaries in Shanghai, Suzhou, and the U.S., Neurophth, a fully integrated company, is striving to discover and develop gene therapies for patients suffering from blindness and other eye diseases globally. Our AAV validated platform which has been published in Nature - Scientific Reports, Ophthalmology, and EBioMedicine, successfully delivered proof-of-concept data with investigational gene therapies in the retina. Our most advanced investigational candidate, NR082 (rAAV2-ND4), in development for the treatment ofND4-mutated LHON, has received orphan drug designations in theU.S. The pipeline also includesND1-mutated LHON, autosomal dominant optic atrophy, glaucoma, wAMD/DME, and other preclinical candidates. Neurophth has initiated the scaling up in-house process in single-use manufacturing technologies to support future commercial demand at the Suzhou facility. To learn more about us and our growing pipeline, visitwww.neurophth.com.

SOURCE Neurophth Therapeutics, Inc.

http://www.neurophth.com

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Neurophth Therapeutics Further Expands Ocular Gene Therapy Expertise with Appointment of Qiutang Li, Ph.D., as Chief Scientific Officer - PRNewswire

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Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them – CNN

They couldn't explain why those afflicted, often in the same family, had recurring fevers, abdominal pain, troublesome rashes and muscle aches. Known as familial Mediterranean fever, the disease often went undiagnosed for years, and it was sometimes fatal.

A similar, but unrelated, mystery fever was initially thought to affect families with Scottish and Irish heritage.

"The pain I felt back then, it moved around. One week the pain was in my leg, and the next week my arm would hurt instead," said Victoria Marklund, 47, a Swedish woman who suffered from TRAPS, or tumor necrosis factor receptor-associated periodic syndrome, a disease first identified in a family of Irish and Scottish descent living in the UK city of Nottingham in 1982.

Her father and grandfather died prematurely from kidney complications, which were likely a consequence of the undiagnosed disorder.

Marklund has now received an effective treatment and lives symptom-free -- largely thanks to the work of one US physician and health researcher, Dr. Dan Kastner, a distinguished investigator at the National Institutes of Health who serves as scientific director of the National Human Genome Research Institute.

"What Dr. Kastner has accomplished is absolutely groundbreaking. The concept of autoinflammatory disorders didn't exist before he identified the cause behind a number of them," said Olle Kmpe, a professor of clinical endocrinology at Karolinska Institutet in Stockholm who is a member of The Royal Swedish Academy of Sciences and chair of the Prize Committee. The academy also selects Nobel laureates.

"His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of disease from which patients previously suffered enormously," Kmpe added.

Breakthrough

Kastner first came across familial Mediterranean fever in a patient with recurring arthritis and high fevers he treated as a rheumatology fellow just months into his first job at the NIH in Bethesda, Maryland, in 1985. That chance diagnosis set him on a 12-year journey to find the gene -- or genes -- responsible for the disease.

"It was known that familial Mediterranean fever was a genetic disease. It was known that it was recessively inherited, but no one knew what the gene was, or even the chromosome," he said.

He traveled to Israel, where he took blood samples from 50 families with familial Mediterranean fever.

It took Kastner seven years to locate the mutation to chromosome 16. It took another five years -- in 1997 -- for Kastner and his team to find the mutated gene itself -- one misprint in a genetic code comprised of 3 billion letters.

After this breakthrough, he stayed at NIH, where he studied undiagnosed patients with similar symptoms. He identified 16 autoinflammatory genetic disorders and found effective treatments for at least 12 of them, establishing a whole new field of medicine.

Now that the full human genome has been mapped, the process of detecting the genetic root of such disorders is quicker, and greater numbers of patients with these rare, unexplained diseases are being helped as a result of Kastner's work.

All-nighters

There are few images in science more iconic than the DNA double helix structure, discovered in 1953 by James Watson and Francis Crick, two years after Kastner was born. As a seventh grader, he once created a version of the twisted ladder shape using jelly beans and pipe cleaners for a science fair.

His work to identify the gene that caused familial Mediterranean fever had its own element of competition. In the summer of 1997, to beat a rival team led by French researchers, Kastner took a last-minute flight from Bethesda, Maryland, where the NIH is based, to Boston to submit his manuscript detailing the gene mutation that caused familial Mediterranean fever by hand to the journal Cell on a Friday afternoon.

These were the days before papers could be submitted with the click of a mouse. He hoped to publish his work first. Ultimately, the two teams published their papers simultaneously in different journals -- both fortunately arriving at the same finding.

"I love that type of thing," he said. "We still have races to the finish, and there's nothing like a good week of all-nighters."

Kastner had discovered that the gene involved in familial Mediterranean fever produces a protein called pyrin. Normally this helps to activate our innate immune system -- our first line of defense to fight bacteria and viruses.

In this case, however, pyrin made the innate immune system become overactive, resulting in fever, pain and joint inflammation. He went on to study patients with similar and more devastating symptoms -- identifying TRAPS and many more rare diseases.

Transforming lives

What has motivated Kastner for five decades is how his work decoding the genetics of inflammation can inform new treatments and ultimately transform patients' lives.

"There's nothing more gratifying in life and nothing more satisfying scientifically," he said. He plans to step down from his role as scientific director at the NIH in the next few months and then focus his efforts on his clinic, where he has over 3,000 patients enrolled and "find yet more disease genes, understand how they work, and develop new treatments."

"Of course, one can never know how long that will last, but I love doing it, and will continue as long as I can."

In more recent work beginning in 2014, Kastner identified and pioneered treatment for a severely debilitating genetic disorder known as DADA2, short for deficiency of the enzyme ADA2 (adenosine deaminase 2), which can cause recurring fevers and strokes starting in childhood. His research has radically improved the life of the daughter of Dr. Chip Chambers.

"She's now at college and the improvement in her quality of life has been dramatic."

Similarly, TRAPS survivor Marklund suffered for years before her diagnosis at the age of 38. Her nephews, who both have TRAPS but have been given medicine from an early age, don't feel the effects of the disease at all, she told The Royal Swedish Academy Of Sciences.

"I doubted many times that anyone would ever figure out what I was suffering from. So now it feels fantastic, to be told what it was, to understand the cause of the disease and that there is medicine that helps."

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Are Gene Therapies the Medicine of the Future? – BioSpace

Over the next 10 years, gene therapies are expected come into their own as a treatment option for a variety of diseases. So far, two such therapies have snagged regulatory approval, Novartis Zolgensma for spinal muscular atrophy, and Sparks Luxturna for a rare form of genetic blindness. More are waiting their turn.

Multiple companies are delving into gene therapy research with hopes of developing a one-time treatment for devastating genetic diseases. Gene therapies offer great reward in the form of treating various devastating diseases, but there are also significant risks. Over the past year, several clinical studies have been halted or scrapped due to safety concerns.

Bay Area-based Audentes Therapeutics had a temporary hold placed on the gene therapy under development for X-linked myotubular myopathy following reports of several patient deaths. That hold has since been lifted by the U.S. Food and Drug Administration. Uniqure also saw a hold placed on its hemophilia B trial after a patient in the study developed liver cancer. The hold was placed weeks after the company announced promising Phase III results at a conference in December.

Despite those risks, hundreds of millions of dollars in research dollars are being invested in gene therapies because of the potential near-curative capabilities the technology could offer. In December, life sciences giant Bayer launched a cell and gene therapy platform within its pharmaceutical division in order to become a leading company within a rapidly emerging and evolving field that offers the potential of life-saving therapies. Eli Lilly also dove into the field in December with the acquisition of Prevail Therapeutics. That deal was expected to extend Eli Lillys research efforts through the creation of a gene therapy program that will be anchored by Prevail's portfolio of clinical-stage and preclinical neuroscience assets.

This week, German scientists reported they were able to use gene therapy to help paralyzed mice run again. The researchers were able to genetically engineer a unique protein dubbed hyper-interleukin-6, which was then able to stimulate the regeneration of nerve cells in the visual system. A few weeks after the treatment, the injured animals were able to walk again.

Scientists in China announced the development of a gene therapy that could potentially reverse the effects of ageing. Initial research was conducted with mice, but if it is proven to be safe, human testing could begin. As Reuters reported, the method involved inactivating a gene called kat7 which the scientists found to be a key contributor to cellular ageing. Researchers used CRISPR/Cas9 to screen thousands of genes for those which were particularly strong drivers of cellular senescence, the term used to describe cellular ageing, Reuters said.

Earlier this month, a public-private partnership in Boston formed to open a new facility to boost advances in cell and gene therapies. This creation of this new facility is being helmed by Harvard University and the Massachusetts Institute of Technology. Those prestigious universities are partnering with industry members such as Fujifilm Diosynth Biotechnologies, Cytivia and Alexandria Real Estate Equities, as well as multiple research hospitals. Part of the goal of this new institute, which is still unnamed at this point, is to boost the supply of materials for research and early clinical studies, provide space for some research and also offer training in equipment used for gene therapies, The Harvard Gazette reported this week.

On Monday, Curadigm, a subsidiary of France-based Nanobiotix, forged a collaboration with Sanofi to assess if that companys Nanoprimer technology is a promising option to significantly improve gene therapy development. The goal of the project is to establish proof-of-concept for the Nanoprimer as a combination product that could improve treatment outcomes for gene therapy product candidates.

Many promising nucleic acid-based therapeutics administered intravenously are limited in their efficacy due to rapid clearance in the liver, which prevents these therapies from reaching the necessary accumulation in target tissues to generate their intended outcomes. Additionally, accumulation in the liver, rather than in the target tissues, can lead to dose-limiting hepatic toxicity, Nanobiotix said in its announcement. The Nanoprimer is designed to precisely and temporarily occupy therapeutic clearance pathways in the liver. Delivered intravenously, immediately prior to the recommended therapy, the technology acts to prevent rapid clearancethereby increasing bioavailability and subsequent accumulation of therapeutics in the targeted tissues.

The Nanoprimer is a combination product candidate that does not alter or modify the therapies it is paired with, which means if the research with Sanofi is successful, Curadigm could seek out other opportunities for its technology.

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CCMB team identifies variants of genes that metabolise drugs – BusinessLine

As India emerges a destination of global choice for clinical trials of various drugs, a study on variants of the gene important for drug metabolism seeks to explore how drugs function across diverse populations.

Dr K Thangaraj and his team from CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, recently published their study of diversity of cytochrome-P450-2C9 (CYP2C9) gene in Pharmacogenomics and Personalized Medicine.

Healthcare is now moving towards personalised medicine. Our studies on the genetic diversity of India will play an important role in this transition, says Dr Rakesh Mishra, Director, CCMB.

The study is important as it seeks to analyse doctor-prescribed dose of drugs based on the gender, age and body mass index (BMI) of patients. However, there are hypersensitive response like rashes, vomiting and nausea.

Individuals in a population have variations in their genes needed for metabolism of a wide range of drugs. Any changes in the sequence of gene may affect the production of protein in human liver. This can cause slower metabolism of a drug and slower or reduced rate of excretion. Many of these drugs have a narrow therapeutic index they are tolerated by human bodies in very specific amounts, according to scientists.

When these drugs are retained in the body for longer, that can lead to toxicity. So, it is important to decide the right dosage for each individual depending on the sequence of their CYP2C9 gene.

Dr Thangarajs team studied the diversity of this gene among 1,488 Indians across 36 population groups, representing different linguistic groups, castes and tribes, among other parameters. They also looked into genes of 1,087 individuals from other countries of South Asia. We found eight new variants of the CYP2C9 gene, making a total of 11 known variants of the gene in South Asia, says Dr Nizamuddin, who is the first author in the study.

They find no correlation between any of these variants with the linguistic and geographical population groups. However, a few Indian populations have more than 20 per cent people with a deleterious variant of the gene. Those with this variant are at a disadvantage in their ability to metabolise drugs. The eight new variants found in this study are also predicted to have similar effect on drug metabolism.

It is important to know the variations in the CYP2C9 gene to help medical practitioners decide the right dosage of medicine for each patient. The knowledge of this variation will also be important for conducting more meaningful clinical trials. This study also suggests that it might not be the best thing to conduct a common clinical trial for the entire world. We need population-specific trials, says Dr Thangaraj, the corresponding author of this paper and presently Director of the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad.

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