Category Archives: Genetic medicine

News Release

Friday, October 18, 2019

HudsonAlpha awarded $7 million to expand national health dataset with uncharted genetic variants.

The All of Us Research Program has selected the HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, to evaluate the use of leading-edge DNA sequencing technologies that could someday improve diagnosis and treatment of many diseases, both common and rare. The National Center for Advancing Translational Sciences (NCATS) is funding the project with $7 million over one year. All of Us and NCATS are parts of the National Institutes of Health.

All of Us will provide one of the worlds most robust platforms for precision medicine research, with a broad range of data to drive new discoveries, said Eric Dishman, All of Us director. Through this partnership with NCATS, well be able to offer approved researchers an even greater depth of genetic information than originally planned, making the resource even more valuable for them and the diverse communities we seek to help.

With this award, HudsonAlpha will use long-read whole genome sequencing technologies to generate genetic data on about 6,000 samples from participants of different backgrounds. Long-read sequencing analyzes DNA in larger segments than standard (short-read) sequencing technologies, exposing genetic variations that may otherwise go undetected. These variations include different types of alterations to the genetic structure, such as duplication, deletion or rearrangement of the building blocks that uniquely make up ones genome and set it apart from others. Everyone has thousands of these genetic variations, most with little known effect. However, researchers are learning more about how some genetic variants underlie certain health conditions or, conversely, increase disease resistance. Understanding the genetic underpinnings of health and disease will help researchers identify more targeted interventions in the future.

This project will allow researchers to better determine the value of long-read sequencing and its strengths and limitations in exploring more elusive parts of the genome. Combined with the 1 million whole genome sequences the program already plans to deliver over the next several years, this additional infusion of genetic information will provide the research community with the largest collection of genomic structural variation data and clinical data ever produced.

Because long-read sequencing can reveal genetic changes associated with rare diseases, this project is an opportunity to assess and potentially refine the technology for advancing research across the many diseases for which there is no treatment, said Christopher P. Austin, M.D., NCATS director. This project illustrates the power of data and technology to accelerate the translation of knowledge into improved health.

The HudsonAlpha team, led by Shawn Levy, Ph.D., brings significant experience in large-scale sequencing projects and in genetic studies on inherited disorders as well as complex conditions, including autism, diabetes, cancer, schizophrenia, degenerative neurological disease and amyotrophic lateral sclerosis(ALS).

We look forward to collaborating with the other All of Us genome centers and the rest of the consortium on this exciting effort, said Dr. Levy. Contributing long-read sequencing data to reveal additional structural variants will enable the scientific community to study human diversity on a tremendous scale.Appreciating the impacts of all types of genetic variation will further unravel the genetic, environmental and behavioral influences of health.

About theAll of UsResearch Program:Themissionof theAll of UsResearch Program is to accelerate health research and medical breakthroughs, enabling individualized prevention, treatment, and care for all of us. The programwill partner with one million or more people across the United States to build the most diverse biomedical data resource of its kind, to help researchers gain better insights into the biological, environmental, and behavioral factors that influence health. For more information, visitwww.JoinAllofUs.organdwww.allofus.nih.gov.

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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NIH funds new All of Us Research Program genome center to test advanced sequencing tools - National Institutes of Health

Sudden Infant Death Syndrome (SIDS), sometimes known as crib death, occurs when an infant under the age of one dies inexplicably.The typically healthy child will often die while sleeping and is the leading cause of death of children between the ages of one month and one year, claiming approximately 3000 lives a year. There has been little known about the cause of SIDS but new research is now showing that some form of SIDS could be linked to a genetic inability to digest milk.

A study out of theUniversity of Washington School of Medicine focused on the "mitochondrial tri-functional protein deficiency, a potentially fatal cardiac metabolic disorder caused by a genetic mutation in the gene HADHA."

It found that newborns with had the genetic mutation are unable toproperly digest some of the fats found in breastmilk, resulting in cardiac arrest. It found that "the heart cells of affected infants do not convert fats into nutrients properly," and once these fats build up they can cause serious heart and heart health issues.

There are multiple causes for sudden infant death syndrome, said Hannele Ruohola-Baker, who is also associate director of the UW Medicine Institute for Stem Cell and Regenerative Medicine. There are some causes which are environmental. But what were studying here is really a genetic cause of SIDS. In this particular case, it involves a defect in the enzyme that breaks down fat.

Lead author on the study Dr. Jason Miklassaid that it was his experience researching heart disease that prompted him to look at the possible link with SIDS. There was one particular study that had noted a link between children who had problems processing fats and who also had cardiac disease that caused him to delve a little deeper.

Miklas andRuohola-Baker teamed up to begin their own research study.If a child has a mutation, depending on the mutation the first few months of life can be very scary as the child may die suddenly,Miklas noted. An autopsy wouldnt necessarily pick up why the child passed but we think it might be due to the infants heart-stopping to beat.

Were no longer just trying to treat the symptoms of the disease, Miklas added. Were trying to find ways to treat the root problem. Its very gratifying to see that we can make real progress in the lab toward interventions that could one day make their way to the clinic.

Ruohola-Baker says their findings are a big breakthrough in understanding SIDS. There is no cure for this, she said. But there is now hope because weve found a new aspect of this disease that will innovate generations of novel small molecules and designed proteins, which might help these patients in the future.

Read Next:Babies May Not Be 'Designed' For Sleeping, According To SIDS Expert

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SIDS May Be Linked To A Genetic Inability To Digest Milk, Study Finds - Moms

Dr Serena will receive the award together with her collaborators Dr Paul Calleja and Dr Ignacio Medina from the University of Cambridge at the University of Bern in Switzerland tonight. Picture via Facebook

KUALA LUMPUR, Oct 18 When Dr Serena Nik-Zainal is not burying her head in cancer genome research, she finds herself outdoors and dabbles in the Chinese martial art of kung fu.

The mother of two, who studies mutation patterns in human DNA at the prestigious University of Cambridge in the United Kingdom, is also a lover of music.

However, medicine is the apparent first love of Dr Serena, who is set to receive the Dr Josef Steiner Award for cancer genome research later tonight. Speaking to Malay Mail, she paid tribute to her father for sparking her interest in the field.

I was inspired by the person who started what is now the National Heart Institute or IJN, she said in an email interview, referring to the late Datuk Dr Nik Zainal Abidin Nik Abdul.

I remember the old building very well, and playing in the small green area outside the front door with the bunga telang (butterfly pea flower).

He was hugely professional, dedicated and determined. But I was also inspired by a mother whom was worldly, solid, resourceful, intelligent in those human qualities, a kind person and a very strong soul, Dr Serena added.

The UK-based Malaysian scientist will be receiving the award with fellow Cambridge collaborators Dr Paul Calleja and Dr Ignacio Medina, at the University of Bern in Switzerland at around 11pm Malaysian time.

According to the University of Cambridges Academic Department of Medical Genetics, she will also be presenting her work under the title Accelerating holistic cancer genome interpretation towards the clinic during the award ceremony.

Based on her research, mutations in cancer tumours can be analysed using new bioinformatic methods which enabled new approaches to targeted therapies.

One may wonder if Dr Serena was ever pressured into pursuing the medical field, since she might have had to live up to her fathers reputation in the medical fraternity.

Dr Nik Zainal who died on October 29, 2007, was known as the cardiologist who brought fame to IJN and the country in general. He was also a member of the team involved in the countrys first coronary bypass surgery in 1982.

Was I pressured into medicine? Yes and no. I would have chosen medicine even if my father was not a doctor.

It has always been a bit of a joke that in Asian households, you have to be a doctor, engineer or a lawyer. But even without that, I suspect I would have ended up a doctor, she explained.

Award a young team effort

Although she has been deeply invested in her research work, Dr Serena said she still does clinical work.

In fact on Monday, I just did a clinic and I still love seeing patients. Thats why I do the research, because I want to fix things for people, she added.

Dr Serena said she was further moved by her patients who have inherited genetic abnormalities or children with learning disabilities and syndromes.

I am a doctor of rare, genetic, inherited disorders. My job is to try to make a diagnosis in these rare cases and to try to ensure that the patients get the best care possible.

Making a diagnosis can be quite tricky. And although there were new technologies available, I found it deeply frustrating to have the most up-to-date data in my hand but not fully understanding it.

So, I decided to try to understand the latest technology that had come along for being able to read the human genome very quickly, called massively parallel sequencing, she said.

She explained that through sequencing, doctors will be able to see all the genetic changes in the human DNA.

And I have never looked back, she added.

It is not just winning the prized dubbed Nobel Prize of cancer research that has sent Dr Serena over the moon, but the fact that her team and her have managed to bag an award at this point of their research work.

There are prizes in research that are awarded every year and many are usually for people whom are very senior in the field.

Prizes like the Dr Josef Steiner award is aimed at middle-career or up-and-coming people (or teams).

So for my team, this is a wonderful boost and an enormous recognition for the kind of work that we do, where we are trying to push bioinformatics towards clinical translation, said Dr Serena.

With this achievement, she is looking forward for accelerate the use of these tools in clinical applications.

She added that this is the beginning to understanding more in the related field.

My work is a speck in the entire genomics field internationally.

[I think] we have been recognised for making interesting, creative analyses and then taking these highly technical bits of genomics and trying to make it clinically useful, so that it will have an impact on patients, she said.

Age of wonders for cancer research

When asked how this research will facilitate the quest to seek a cure for cancer, Dr Serena said the research looks at the entire genome sequence in human cancers, three billion building blocks, or base pairs.

By having a full map of all the genetic changes in cancer, because cancer are highly mutated entities, we can know exactly what the causes are of each persons individual cancer.

We are more likely to treat a patient more effectively and offer the patient a better quality of life, she explained.

She also pointed out that research on cancer has progressed tremendously because cancer research is funded very well.

Even in the decade that she had been doing this, Dr Serena has witnessed changes that are astonishing.

When I started doing whole genome sequencing, it took about three months to get a whole cancer genome. Today, we can do it in one day.

We still do not understand what initiates cancer, which ones do badly and do well.

How cancer cells interact with the other cells in our tissues. There is plenty more to do, and the genome is only one aspect. More yet to learn, she said.

She attributed the success of her research to patients who participated in sharing their materials, tutors, colleagues and collaborators worldwide, as well as charity organisations that had funded her research, training and grants to pursue her interests.

When I receive this award, it is truly on behalf of and due to a wonderful group of people as this achievement does not come from the work of only one person.

She has her family to thank, Dr Serena added that her older brother, Dr Nik Halmey, a cardiologist at Gleneagles Hospital here has always looked out for her.

Apart from her family in Malaysia, one of her biggest supporters is her Irish husband, Dr Eoin OBrien, who is a geriatrician and stroke physician.

He is a very kind, a very solid doctor and a rock in my life. I have two wonderfully energetic children, a 15-year-old boy and an 11-year-old girl. They keep me very busy, she added.

Dr Serena also said that she is slowly building links with her Malaysian counterparts at Universiti Sains Malaysia in Kelantan.

I hope to be part of the process of getting it going, back home, she said.

I have since been collaborating with another Malaysian clinician scientist, Dr Neil Rajan, and we have a scientific paper coming soon. We are so pleased to be flying the Malaysian flag on this paper!

Read more:
Memories of bunga telang: Award-winning Dr Serena Nik-Zainal on how cardiologist dad inspired life in medicine - Malay Mail

Article In Brief

Parkinson's disease specialists and patient advocacy groups have teamed up to promote greater education around the value of genetic testing for Parkinson's disease patients.

The field of genetic research for Parkinson's disease (PD) is evolving rapidly, as access to testing becomes more readily available and a growing number of novel therapies are in development and recruiting for clinical trials. In response, experts in neurology and genetics are calling for expanded education of medical professionals, patients, and the public to ensure accurate information, well-informed decision making, and ultimately better research.

One such initiative by neurologists, genetic counselors, and research staff from Indiana University, Northwestern University, and the Michael J. Fox Foundation (MJFF), has been a proposal to the AAN, outlining a widespread educational partnership targeting general neurologists and the patient community that would accompany efforts by the MJFF to offer greater access to no-cost genetic testing.

Therapeutic development for PD is entering a new and important realm of personalized medicine, said Tanya Simuni, MD, director of the Parkinson's Disease and Movement Disorders Center at Northwestern University, and a member of the nine-person team that developed the proposal. Although a single gene variant is not the cause of disease in the majority of individuals, studies of the small percent of mutation carriers have allowed better understanding of the biology of both genetic and sporadic forms of the disease, she said.

The MJFF and other organizations are working to increase awareness about PD genetics and availability of testingand neurologists have a key role to play in these efforts, Catherine Kopil, PhD, director of research partnerships at MJFF, and Tara Hasting, senior associate director of patient engagement at MJFF, wrote in an email to Neurology Today.

Professionals need up-to-date, structured informational and educational tools to share with patients, they said, specifically as a new MJFF initiative will be offering no-cost, remote targeted PD genetic testing, return of results, and telemedicine genetic counseling for individuals who are at increased risk of carrying the most common PD genetic mutations and who ultimately could qualify to participate in clinical trials. Genetic testing is a complex, expensive, and sensitive topic in any field of medicine, they added.

A consistent message is necessary for patients and families, specifically from neurologistswho will often be on the frontlines of the discussionfor addressing both positive and negative results, the genetic counselors and project managers from the Indiana University School of Medicine pointed out.

Clinical practice guidelines for genetic testing in PD have been limited thus far, Tatiana Foroud, PhD, chair of the department of medical and molecular genetics at Indiana University School of Medicine, said, but that is changing as interest and research in this field grows. As of today, the two genes that are the focus for current trials are GBA and LRRK2, both of which are associated with the more typical, later onset PD.

In the past, knowledge of an individual's mutation status did not significantly affect the clinical care for the majority of PD patients. However, there are ongoing clinical trials that are recruiting PD patients with a mutation in LRRK2 or GBA. Based on the opportunity to participate in ongoing clinical trials, individuals with a strong family history of PD and/or particular ethnic background may want to consider genetic testing for LRRK2 or GBA mutations, Dr. Foroud said.

Genetic discoveries have been revolutionizing PD for the past two decades, the proposal team wrote in an email to Neurology Today, but the new drugs in development are particularly exciting. Our ultimate success will require close collaboration between the scientists, the neurology professional community, patient advocacy organizations, and obviously patients.

In conversations with Neurology Today, neurologists who treat PD and neurogeneticists echoed the call for increased educational programs targeting both the neurologist and the patient and caregiver communities to accompany the ever-changing landscape of PD genetic research.

For decades, and certainly while I was training, we were told that Parkinson's wasn't really a genetic disorder. Now, as a field, we are increasingly aware of the importance of the genetic contribution to PD, said Claire Henchcliffe, MD, DPhil, vice chair of clinical research and chief of neurodegenerative disorders at Weill Cornell Medicine.

The percentage of patients with a monogenic mutation accounting for PD is still in the minority, she noted, but the more we know, the more complex the story becomes. I think what makes it so complicated to educate patientsand neurologists as wellis that we've already got different modes of inheritance that we have to talk about in terms of monogenic Parkinson's, such as autosomal recessive or autosomal dominant. On top of that we've got issues of penetrance and the complexity of multiple risk alleles. So this is not your genetics 101, this is really complicated. Dr. Henchcliffe said it would be helpful to have guidelines or structured main talking points for neurologists and other clinicians to use with their PD patients.

Joshua M. Shulman, MD, PhD, associate professor in the departments of neurology, molecular and human genetics, and neuroscience at the Baylor College of Medicine, agreed that the field is changing very quickly, and although it is still not routine practice to test or recommend PD patients for genetic testing, the conversation is shifting as the number of clinical trials grows.

Currently, experts told Neurology Today that most of the patients they recommend for genetic testing are those with suspected LRRK2 or GBA mutation who have a higher probability of qualifying for clinical trials, as well as those with atypical presentation or early age of onset.

There are disease-specific and context-dependent issues that arise with genetic testing for PD, which is still a relatively new field for many neurologists, Dr. Shulman said. What's interesting to consider, he added, is that many clinical trials are currently restricted to GBA and LRRK2 forms of PD, but might that change in the next few years?

There are many other genetic variants that have been linked to Parkinson's disease. So one might imagine that we could see other trials on the horizon where individuals with specific forms of the disease will be recruited to such trials. Further, there is increasing evidence that specific genetic variants can provide clinically valuable prognostic information about certain disease-related complications or rate of progression, for example.

Patients need to have a uniform set of data and terminology in this delicate area of science, Christopher G. Goetz, MD, FAAN, director of the Parkinson's disease and movement disorders program at Rush University Medical Center, said. In my experience, I find that misinterpretation, fear, and guilt are common among patients who access genetic information, and they must have professional guidance to place the information in a context that is useful.

He added, If the AAN gets involved with such programs, I urge an insistence on responsible pre- and post-testing professional support that addresses the individual's concerns in addition to the actual testing. Broad-based testing without this type of support will not advance the field and in fact could be a disservice in my view.

Other important areas for educational initiatives, Dr. Shulman suggested, for neurologists particularly are going to have to do with who should be tested, are which specific genes and variants should they be tested for, how to communicate that information back responsibly, and what the thresholds are for bringing in other genetic expertise, such as a clinical geneticist or genetic counselor.

There are many educational challenges to address on the patient side as well, Dr. Shulman said, such as the nuanced discussions with patients and family members about risk. Knowing that your Parkinson's disease is caused by the gene LRRK2 may have implications for significant risk associated with carrier states in family members. In the case of other genetic variants, such as GBA, the risk to family members is much lower. It can be harder to convey this more modest risk to family members and the public, he said, and this is one area where education could help.

Evidence is accumulating that patients and their families want this type of genetic information, Dr. Shulman said, which raises the question of whether we should be testing more comprehensively for possible genetic contributions to PDand if we're going to do that, what specific genetic variants should we be looking for and how do we communicate those results in an ethical and responsible manner?

A lot of the emphasis of genetic testing in the past has been solely for research or to better understand the pathways that play in PD pathogenesis, said Dr. Henchcliffe, adding that the results were not generally seen as being actionable. Now, I think the really exciting thing is that we can offer the testing in an era where we can start to do something about it. Although we don't have treatments that are yet FDA approved for specific genetic subtypes of Parkinson's, there are several clinical trials that are attempting to test such genetically targeted therapies. So I think that this is really an area for optimism in terms of advancing treatments for Parkinson's.

Still, she continued, this means the onus is on us as a medical community to provide our patients with PD with the information that they need in order to take the next step, especially as more organizations and consortia are beginning to offer testing and making it more widely available.

Depending on the specific type of test that's going to be employed, neurologists, patients, and families need to understand what they're getting into and what might be discoveredand also what might not be discovered, Dr. Shulman said. In other words, there is still an incomplete understanding of PD genetics.

So when we don't find that somebody has a genetic cause for their disease, that doesn't mean it's not genetically influenced, it just may mean that it's not found on one of the tests that we have available, Dr. Shulman said.

An important question to consider then, he added, is: How do we match genetic testing in clinical practice with a rapidly changing fieldwhere almost every month, new genetic findings are emerging and any test we do today may rapidly be out of date?

At this point, Dr. Goetz said, individuals at high-risk for monogenic specific forms of PD are prime candidates for testing, since they are most likely to benefit from gene-based therapy. On the other hand, The broad movement to gene-test even when specific treatments are not available is based on the premise that new gene-specific therapies will eventually be developed and patients want to be ready. The alternate approach, however, is to develop the putative therapies first and then solicit patients to come forward and be tested. In this case, the developer of the therapy would take the burden of testing and counseling whereas with the proposed be ready approach, foundations, governments, or agencies, including the AAN, take on the responsibility.

We need broad engagement with the neurologic community and patient communities to understand the best way to proceed. I think that's an important role that the AAN can play, Dr. Shulman said.

Dr. Simuni has served as a consultant for Acadia, Abbvie, Accorda, Adamas, Allergan, Amneal, Anavex, Aptinyx, Blue Rock Therapeutics, Denali, General Electric ( GE), Neuroderm, Neurocrine, Sanofi, Sinopia, Sunovion, TEVA, Takeda, Voyager, US World Meds, Parkinson's Foundation, and the Michael J. Fox Foundation for Parkinson's Research; has served as a speaker and received an honorarium from Acadia and Adamas; is on the scientific advisory board for Anavex, Neuroderm, Sanofi, and MJFF; has received research funding from the NINDS, Parkinson's Foundation, MJFF, Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, Abbvie and IMPAX. Dr. Goetz has received honoraria from Oxford Biomedica; grants/research funding to Rush University Medical Center from NIH, Department of Defense, and Michael J. Fox Foundation; directs the Rush Parkinson's Disease Research Center supported by the Parkinson's Foundation; royalties from Elsevier Publishers, Oxford University Press, Wolters Kluwer.

Originally posted here:
Experts Call for Expanded Educational Initiatives on... : Neurology Today - LWW Journals

-- Improvements on functional measures seen in all three participants --

-- Significant reduction in creatine kinase maintained over nine months --

-- Results follow positive and robust expression and biomarker data presented earlier in 2019 --

CAMBRIDGE, Mass., Oct. 04, 2019 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced the nine-month functional results from three Limb-girdle muscular dystrophy Type 2E (LGMD2E) clinical trial participants who received SRP-9003. SRP-9003 is an investigational gene therapy intended to transduce skeletal and cardiac muscle with a gene that codes for the full-length, native beta-sarcoglycan protein, the lack of which is the sole cause of LGMD2E.

In Cohort 1 of the SRP-9003 study, three participants ages 4-13 were treated with an infusion of SRP-9003 at a dose of 5x1013vg/kg. Improvements in functional outcomes were observed at day 270 (nine months) for all three participants.

We have now observed consistent functional improvements, in addition to high levels of expression of the missing protein of interest and strong results in related biomarkers, in both of our first cohorts for Duchenne muscular dystrophy (SRP-9001) and LGMD2E (SRP-9003). We intend to test one higher dose of SRP-9003 in LGMD2E participants, select our clinical dose and then advance our SRP-9003 program, along with our other five LGMD programs, as rapidly as possible, said Doug Ingram, Sareptas president and chief executive officer. With the results of our first LGMD2E cohort, Sarepta continues to build its gene therapy engine, an enduring model created to design, develop and bring to the medical and patient community transformative therapies for those living with, and too often dying from, rare genetic disease.

At Day 270, mean creatine kinase (CK) was significantly reduced compared to baseline. CK is an enzyme biomarker strongly associated with muscle damage.

At Day 270, all three participants showed improvements from baseline across all functional measures, including the North Star Assessment for Dysferlinopathy (NSAD), time to rise, four-stair climb, 100-m walk test and 10-meter walk test. These results are distinctly different from what an age-matched, natural history group would predict.

No new safety signals were observed and the safety profile seen to date supports the ability to dose escalate in the next cohort of the study. As previously disclosed, two participants in the study had elevated liver enzymes, one of which was designated a serious adverse event (SAE), as the participant had associated transient increase in bilirubin. Both events occurred when the participants were tapered off oral steroids and, in both instances, elevated liver enzymes returned to baseline and symptoms resolved following supplemental steroid treatment.

LGMD2E is a devastating neuromuscular disease with no current treatment options so we are very pleased to observe a functional improvement in study participants who received SRP-9003, said Jerry Mendell, M.D., principal investigator at the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Childrens Hospital and lead investigator for the study.

Sarepta had previously shared expression results from the study, which found that in two-month post-treatment muscle biopsies, clinical trial participants showed a mean of 51% beta-sarcoglycan positive fibers, as measured by immunohistochemistry (IHC), substantially exceeding the pre-defined 20% measure for success. Mean fiber intensity, as measured by IHC, was 47% compared to normal control.

About SRP-9003 and the Phase I/IIa Gene Transfer Clinical Trial

SRP-9003 uses the AAVrh74 vector, which is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat peripheral neuromuscular diseases. As a rhesus monkey-derived AAV vector, AAVrh74 has lower immunogenicity rates than reported with other common human AAV vectors. The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with LGMD2E, many of whom die from pulmonary or cardiac complications.

This first-in-human study is evaluating a single intravenous infusion of SRP-9003 among children with LGMD2E between the ages of four and 15 years with significant symptoms of disease.

About Limb-Girdle Muscular Dystrophy

Limb girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs.

Patients with LGMD2E begin showing neuromuscular symptoms such as difficulty running, jumping and climbing stairs before age 10. The disease, which is an autosomal recessive subtype of LGMD, progresses to loss of ambulation in the teen years and often leads to death before age 30. There is currently no treatment or cure for LGMD2E.

Sarepta has five LGMD gene therapy programs in development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B and LGMD2L, and holds an option for a sixth program for LGMD2A.

About Sarepta Therapeutics

Sarepta is at the forefront of precision genetic medicine, having built an impressive and competitive position in Duchenne muscular dystrophy (DMD) and more recently in gene therapies for Limb-girdle muscular dystrophy diseases (LGMD), MPS IIIA, Pompe and other CNS-related disorders, totaling over 20 therapies in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. Sarepta is fueled by an audacious but important mission: to profoundly improve and extend the lives of patients with rare genetic-based diseases. For more information, please visit http://www.sarepta.com.

Forward-Looking Statements

This press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements regarding our intention to test one higher dose of SRP-9003 in LGMD2E participants, select our clinical dose and then advance our SRP-9003 program, along with our other five LGMD programs, as rapidly as possible; Sarepta continuing to build an enduring gene therapy model created to design, develop and bring to the medical and patient community transformative therapies for those living with rare genetic disease; the safety profile of SRP-9003 seen to date supporting the ability to dose escalate in the next cohort of the study; SRP-9003 being an ideal candidate to treat peripheral neuromuscular diseases; the potential benefits of the AAVrh74 vector and the MHCK7 promoter; and our mission to profoundly improve and extend the lives of patients with rare genetic-based diseases.

These forward-looking statements involve risks and uncertainties, many of which are beyond Sareptas control. Known risk factors include, among others: success in preclinical testing and early clinical trials, especially if based on a small patient sample, does not ensure that later clinical trials will be successful, and initial results from a clinical trial do not necessarily predict final results; the data presented in this release may not be consistent with the final data set and analysis thereof or result in a safe or effective treatment benefit; different methodologies, assumptions and applications Sarepta utilizes to assess particular safety or efficacy parameters may yield different statistical results, and even if Sarepta believes the data collected from clinical trials of its product candidates are positive, these data may not be sufficient to support approval by the FDA or foreign regulatory authorities; Sareptas ongoing research and development efforts may not result in any viable treatments suitable for clinical research or commercialization due to a variety of reasons, some of which may be outside of Sareptas control, including possible limitations of company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, and regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover our product candidates; and even if Sareptas programs result in new commercialized products, Sarepta may not achieve any significant revenues from the sale of such products; and those risks identified under the heading Risk Factors in Sareptas most recent Annual Report on Form 10-K for the year ended December 31, 2018, and most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.

Any of the foregoing risks could materially and adversely affect the Companys business, results of operations and the trading price of Sareptas common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.

Internet Posting of Information

We routinely post information that may be important to investors in the 'For Investors' section of our website at http://www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Source: Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.

Investors:Ian Estepan, 617-274-4052iestepan@sarepta.com

Media:Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics Announces Positive Functional Results from the SRP-9003 (MYO-101) Gene Therapy Trial to Treat Limb-Girdle Muscular Dystrophy Type...

Friday, October 4, 2019

Recognition of outstanding Purdue Veterinary Medicine facultyand alumni at the annual Awards Celebration was a high point of the 2019 PurdueVeterinary Conference. The event on Wednesdayevening, September 18, honored the following College of Veterinary Medicine facultymembers and distinguished alumni.Congratulations to each of these award winners!

Faculty Awards

Dr. John Christian | Raymond E. Plue Outstanding Teacher AwardAssociate Professor of Veterinary Clinical PathologyLab Director and Section Chief of Clinical Pathology

Dr. Stephanie Thomovsky | Zoetis Distinguished Teacher AwardClinical Associate Professor of Veterinary Neurology

Dr. Steve Adams | Excellence in Service AwardProfessor of Large Animal Surgery

Dr. Larry Adams | Alumni Faculty Award for ExcellenceProfessor and Co-section Head of Small Animal Internal Medicine

Dr. Jonathan Townsend | Alumni Outstanding Teaching Award Clinical Assistant Professor of Dairy Production MedicineDirector of Extension Programs

Dr. Joanne Messick | Excellence in Teaching AwardProfessor of Veterinary Clinical Pathology

Dr. Mohamed Seleem | Excellence in Research AwardSection Head of Microbiology and ImmunologyProfessor of Microbiology

Dr. GuangJun Zhang | Zoetis Award for Veterinary ResearchExcellenceJohn T. and Winifred M. HaywardAssociate Professor of Genetic Research, Genetic Epidemiology and ComparativeMedicine

Dr. Darryl Ragland | Faculty Excellence in Diversity and Inclusion Award Associate Professor of Food Animal Production MedicineSection Head of Production Medicine

Dr. Janice Kritchevski | Resident Mentor Award Professor of Large Animal Internal MedicineSection Head of Production Medicine

Distinguished Alumni Awards

Dr. Timothy Adams (PU DVM 86) | Distinguished Alumnus AwardRetired Brigadier General with the United States Army

Dr. Tom Gillespie (PU DVM 79) | Distinguished Alumnus AwardRetired Swine Practitioner and 2018 Master of the Pork Industry

Writer(s): Susan Xioufaridou | pvmnews@purdue.edu

Link:
Celebration Spotlights Award-winning Faculty and Alumni - Purdue Veterinary News

By examining heart cells derived from the skin samples of seven family members, researchers at UC San Diego School of Medicine discovered that many genetic variations known to influence heart function do so because they affect the binding of a protein called NKX2-5.

Genome-wide association studies have uncovered more than 500 genetic variants linked to heart function, everything from heart rate to irregular rhythms that can lead to stroke, heart failure or other complications. But since most of these variations fall into areas of the genome that dont encode proteins, exactly how they influence heart function has remained unclear.

By examining heart cells derived from the skin samples of seven family members, researchers at University of California San Diego School of Medicine have now discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

The study is published September 30, 2019 in Nature Genetics.

NKX2-5 is a transcription factor, meaning it helps turn on and off genes in this case, genes involved in heart development. To do this, NKX2-5 must bind to non-coding regions of the genome. Thats where genetic variation comes in.

NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function, said senior author Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine at UC San Diego School of Medicine. As a result, we are finding that multiple heart-related traits can share a common mechanism in this case, differential binding of NKX2-5 due to DNA variants.

The study started with skin samples from seven people from three generations of a single family. The researchers converted the skin cells into induced pluripotent stem cells (iPSCs) as an intermediary. Like all stem cells, iPSCs can both self-renew, making more iPSCs, and differentiate into a specialized cell type. With the right cocktail of molecules and growth factors, the researchers directed iPSCs into becoming heart cells.

These heart cells actually beat in the laboratory dish, and still bear the genetic and molecular features of the individuals from which they were derived.

Frazer and team conducted a genome-wide analysis of these patient-derived heart cells. They determined that NKX2-5 can bind approximately 38,000 sites in the genome. Of those, 1,941 genetic variants affected NKX2-5 binding. The researchers investigated the role of those variants in heart gene function and heart-related traits. One of the genetic variants was associated with the SCN5A gene, which encodes the main channel through which sodium is transported in heart cells.

Since related individuals tend to share similar genetic variants, the team was able to validate their findings by analyzing the same variants in multiple samples.

People typically need a large number of samples to detect the effects of common DNA variants, so we were surprised that we were able to identify with high confidence these effects on NKX2-5 binding at so many sites across the genome with just few people, said first author Paola Benaglio, PhD, a postdoctoral researcher in Frazers lab.

Yet, she said, this finding may just be the tip of the iceberg.

There are probably a lot more genetic variants in the genome involved with NKX2-5 as well as with other important cardiac transcription factors, Frazer said. We identified almost 2,000 in this study, but thats probably only a fraction of what really exists because we were only looking at seven people in a single family and only at one transcription factor. There are probably many more variants in gene regulation sites across the entire population.

Not only does the team plan to further investigate cardiovascular genetics, they also have their sights set on other organ systems.

We are now expanding this same model system to look at many different transcription factors, across different tissue types, such as pancreas and retina epithelia, and scaling it up to include more families, Benaglio said.

Co-authors include: Agnieszka DAntonio-Chronowska, William W. Young Greenwald, Margaret K. R. Donovan, Christopher DeBoever, He Li, Frauke Drees, Sanghamitra Singhal, Hiroko Matsui, Kyle J. Gaulton, Erin N. Smith, Matteo DAntonio, Michael G. Rosenfeld, UC San Diego; Wubin Ma, Feng Yang, Howard Hughes Medical Institute and UC San Diego; Jessica van Setten, University Medical Center Utrecht; and Nona Sotoodehnia, University of Washington.

This research was funded, in part, by the National Institutes of Health (grants HG008118, HL107442, F31HL142151, T32GM008666, P30CA023100, HL116747, HL141989, R01DK114650, DK018477, DK039949), National Science Foundation (grant 1728497), California Institute for Regenerative Medicine (grants GC1R-06673-B, TG2-01154), Swiss National Science Foundation (postdoc mobility fellowships P2LAP3-155105,P300PA-167612), ADA (grant 1-17-JDF-027) and Howard Hughes Medical Institute.

UC San Diegos Studio Ten 300 offers radio and television connections for media interviews with our faculty. For more information, email .(JavaScript must be enabled to view this email address).

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Skin-Cells-Turned-to-Heart-Cells Help Unravel Genetic Underpinnings of Cardiac Function - UC San Diego Health

PITTSBURGH (KDKA) In a dish sits a human liver.

Not removed from a person, but created from scratch.

Its not like wahoo and the next morning you think, ah, Im gonna make a human liver,' says Dr. Alejandro Soto-Gutirrez of the Pittsburgh Liver Research Center.

It took five years of trial and error but using stem cells, genetic and tissue engineering, organ cultures and a team of experts in these areas, the researchers have come up with this.

Alexandra Collin de Lhortet, Ph.D. of the University of Pittsburgh School of Medicine explains the process.

A rat liver gets stripped of its cells so that only the connective tissue remains.

From a small piece of human skin, the scientists pluck out stem cells and coax them into becoming human liver cells and the cells are collected.

Then theyre injected into the chamber, called a bioreactor, where they take up residence in the empty rat liver.

The entire process from gathering the cells to make a liver, to get to this point, where you have an actual mini human liver in a bioreactor, takes several months.

It will stay alive, or viable, for only a few days.

But in that short time, the researchers can try different medicines to treat the diseased liver.

You could test any sort of therapeutic by simply injecting this chemical through the system, says Dr. Collin.

In the past, animal livers played a role in this kind of research but human livers didnt always respond in the same way.

With this system, the cells have had genetic modification to recreate diseases, for example, fatty liver, a growing problem in the United States.

This technology has the potential for personalized medicine. From your skin cells, they could grow your own mini liver to figure out which medicines would work for you.

I believe its a very good biological tool to screen treatments that are not otherwise being tested in humans themselves because its dangerous, says Dr. Soto.

As its designed, it would be a long stretch to create livers for transplantation.

If you mean how far we are to make actual livers for people, I think we are very far away. Were probably many years away. But this is a good step, Dr. Soto says.

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After 5 Years Of Trials, Doctors Create Human Liver From Scratch - CBS Pittsburgh

AUSTIN, Texas, Oct. 3, 2019 /PRNewswire/ -- Partners in Health (https://partners-in-health.com/) announced it would celebrate its one-year anniversary with an upcoming Open House event. All past and present patients of Dr. Rhodes are welcome to attend, as is anyone interested in learning about the practice and her medical colleagues. The Open House is slated for Thursday, October 10 from 5:30 to 8:00 p.m., at 631 West 38th Street, Suite 5, and will include snacks from Austin's famous Tacoman 512 Taco Truck, wine and beverages, healthy living door prizes and more. Dr. Rhodes asks that guests rsvp online before attending.

"It's almost unbelievable to me that Partners in Health has reached its first anniversary," said Dr. Rhodes. "I started the concierge medical practice as a way to be more deeply involved in my patients' care a way to provide them 24/7 personalized healthcare. It was a dream of mine, and I'm so excited to celebrate that dream's reality."

Partners in Health: Precision Genomic Medicine

Partners in Health is a private concierge health practice that features the services of internist physician Dr. Rhodes and her staff, and is one of the first Internal Medicine practices in the Austin area to integrate a precision genomic medicine program (genetic testing) into its overall care plan.

Precision Medicine is a new medical approach that allows doctors to tailor their care to each patient's unique genetic makeup, giving doctors important tools that allow them to prevent, diagnose and treat a wide range of diseases. The science behind genomic medicine continues to evolve rapidly, but is based on the basic concept of the human genetic blueprint. The body is made up of trillions of cells that are defined by 3.2 billion DNA base pairs. Those pairs are the foundation of body health and wellness.

Until recently, genetic sequencing was a costly technique that was rarely covered by insurance and reserved for severely ill patients. It is now more widely understood by health professionals that predictive testing not only saves money over the long term, but also saves lives. Dr. Rhodes is currently working with a variety of high quality, FDA-approved labs who use advanced sequencing techniques to provide scientifically proven, actionable information that she can use in her patients' care.

"One of my goals for the concierge practice has always been to include Precision Genomic Medicine," said Dr. Rhodes. "I'm working toward 100 percent participation in this program over the next year, as it is one of the easiest actions patients can take to understand and improve their overall health. When we know what problems we should be looking for, it's much easier to find and treat them."

Learn more about Dr. Rhodes and Genomic Medicine HERE.

About Partners in Health

Partners in Health is a personalized internal medicine concierge practice created by Dr. Roxana Rhodes to serve the Austin community. A native Texan and third generation Texas physician, Dr. Rhodes has over two decades experience as primary care doctor and an educator. Partners in Health reflects Dr. Rhodes guiding belief that all patients experience far better health outcomes when patients are engaged in their own care, in an ongoing compassionate and collaborative effort with their healthcare providers. Learn more at: http://www.Partners-in-Health.com.

Media Contact:

Roxana Rhodes, MD512-423-1831223598@email4pr.com

SOURCE Dr. Roxana Rhodes

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Dr. Roxana Rhodes Marks One Year Anniversary of Concierge Medical Practice With Open House Celebration - PRNewswire

The child was critically ill. The treating team at Children's National Hospital in Washington, DC, was stumped and worried that time was running out. Every test was coming back negative.

Genetics was called in to look for chromosomal mutations that might suggest the source of the problems. The geneticist recommended whole-exome sequencing, which tells a story based not only on all of the child's genes, but on two additional sources as well: the mother's and the father's genes.

They found something they weren't looking for. The father, the worried man in the waiting room who raised this child, wasn't the biological father. In genomics it's called an "incidental finding," and it raises huge ethical questions: Do you reveal this to the parents? Only to the mother? Or, if the results don't affect the child's care, do you even tell anyone?

In this case, the team called on the hospital's ethics committee for help.

Monisha Samanta Kisling, MS

"What made it really complicated here is that the father was actually the primary caregiver and was really, really involved with the child," explains Monisha Samanta Kisling, MS, a genetic counselor who has worked at Children's National for 7 years. Plus, the father was the legal parent and responsible for the family as a provider, including securing the child's health insurance. Disclosing this information could have a lasting, lifelong effect.

"He has dedicated his life to and does everything for the child. You're really at risk of causing potential serious conflict for this family, and potentially for this kid who really needs that support system," Kisling says.

If you think this scenario is an outlier, you're mistaken. Various studies have estimated rates of false paternity at between 1% and 10%.[1]

The field of genomics calls misattributed paternity or in some cases, simply paternity a "secondary" or incidental finding. Perhaps, but it's certainly difficult to ignore.

"In a lot of cases, it's just very hard to hide that information with the report that you have," Kisling explains, because the variants that a geneticist discovers in the child's DNA don't match up at all with the father's genes. "If the child didn't inherit any of the variance from the father, that would throw in some question marks, right?"

Paternity might be incidental, but it's clearly significant. This information whether a father is truly a child's biological father can change families in an instant.

Whether to disclose poses a dilemma that can feel fraught. Telling a man that he's not the father of his child can have devastating consequences: He might leave the family. The standard in pediatrics is to practice medicine "in the best interest of the child"[2]; first and foremost is the child's well-being. That means keeping the focus on the child and their future.

Still, because there are really no data about how these shocking disclosures affect families, doctors are truly in the dark about how to handle these tricky scenarios.

"It's hard to make these decisions because we may not know the families that well. We don't necessarily know what's the right decision for them," Kisling says. She believes clinics should approach each family with fresh eyes, because every couple is different.

"I think withholding information can feel paternalistic," Kisling says. "We don't want to say, 'Hey, I don't think you can handle this information.' That's not necessarily our judgment call to make. Overall, it's just a really, really tough decision."

Read the original here:
'You're Not the Father': A Moral Dilemma in Genetic Testing - Medscape