SPTLC1

NEW YORK--( BUSINESS WIRE )-- RTW Charitable Foundation (“RTWCF”) announced today that it has awarded $900,000 in research grants to support six research studies. These studies aim to drive transformational progress in genetic therapies and align with RTWCF’s mission to power community initiatives and scientific research to improve the health of underserved communities. Grant Recipients The following studies and researchers each received $150,000 research grants from RTWCF: “ Establishing gene replacement therapy for NEDAMSS, an ultra-rare neurological disorder caused by mutations in the IRF2BPL gene” (Kathrin Meyer, Nationwide Children’s Hospital, Columbus, OH). “ Optimizing AAV-SPL gene therapy for sphingosine phosphate lyase insufficiency syndrome” (Julie Saba, University of California, San Francisco, San Francisco, CA). “Gene therapy for SURF1-related Leigh Syndrome” (Steven Gray, The University of Texas Southwestern, Dallas, TX). “ Safety and toxicity assessment of AAV-based gene therapy for creatine transporter deficiency” (Jagdeep Walia, Queen’s University, Kingston, Ontario, Canada). “Advanced therapeutics for SELENON-related myopathy” (Alan Beggs, Boston Children’s Hospital, Boston, MA). “ Preclinical studies of ASO therapy for SPTLC1-related hereditary sensory neuropathy” (Haiyan Zhou, University College London, London, UK). “ Despite considerable advancements in gene and cell therapies that deliver more targeted and effective treatments for rare diseases, a significant amount of additional research is still required to move these advances out of the lab and safely to patients,” said Juan Carlos López, PhD, Managing Director, Research Grants, RTW Charitable Foundation. “ RTW Charitable Foundation is proud to provide financial and scientific support to these six incredible researchers and their respective studies. We believe that each of these studies will help expedite the development of gene therapies for rare and ultrarare diseases, and greatly improve the lives of individuals with unmet medical needs.” Grant Recipient Commentary Julie Saba, MD, PhD, commented : “ I am honored and grateful to receive this award from RTWCF, which will support studies to optimize gene therapy for sphingosine phosphate lyase insufficiency syndrome. This newly recognized inborn error of metabolism leads to kidney failure in most of the affected children, causing more than half of them to die in their first years of life. While kidney transplantation can be lifesaving, it is invasive, costly, unavailable to many, and does not address the many other serious consequences of the disorder. Gene therapy offers a potentially lifesaving alternative treatment. The studies undertaken with RTWCF funding should improve our gene therapy potency, allowing us to advance to toxicology studies and clinical trials. I appreciate RTWCF’s dedication to advancing research in ultrarare diseases, which are overwhelmingly underfunded. Every child deserves personalized therapy!” Alan Beggs, PhD, commented: “ Our group has studied a neuromuscular condition called Multiminicore Disease or Rigid Spine Muscular Dystrophy for many years to understand how mutations of a gene called SELENON lead to weakness. We are now on the cusp of translating our laboratory experiments into a treatment that can be tested in patients. I’m thrilled that support from the RTWCF is helping us to work towards developing a next-generation gene therapy candidate designed for eventual testing in a clinical trial.” Haiyan Zhou, MD, PhD, commented: “ We are extremely grateful for the generous award from RTWCF. This grant serves as a vital catalyst in advancing our groundbreaking work on a novel nucleic acid therapy designed for an ultrarare neurodegenerative condition, currently devoid of effective treatment options. The crucial support from RTWCF will propel the preclinical development and hasten the clinical translation of this experimental therapy. Moreover, this award will play a pivotal role in elevating the impact of our translational genetic therapy program at the Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre. It also contributes to the growth of the UK platform for nucleic acid therapy in rare diseases.” To date, RTWCF has awarded over 20 research grants, totaling over $3 million in funding. In addition to delivering financial resources, RTWCF also provides grant recipients with hands-on scientific support, helping them improve or further develop their research and research tools and identify new therapeutic targets. About RTW Charitable Foundation Founded in 2018 as the charitable foundation arm of RTW Investments, LP, RTW Charitable Foundation works to power community initiatives and scientific research to improve the health of underserved communities. The Foundation is able to provide capital, manpower, and logistical support to help scientists push such projects forward. In addition, the Foundation aims to assist in advocacy, disease awareness and directly support organizations and communities in New York City. To learn more, visit www.rtwcf.org .

NIH Senior Scientist Dr. Carsten Bönnemann examines patient Claudia Digregorio/Photo courtesy of NIH Six years ago, a young Italian woman named Claudia Digregorio came to a team of researchers at the National Institutes of Health (NIH) and Uniformed Services University (USU), and potentially opened a whole new window into understanding Amyotrophic Lateral Sclerosis (ALS). Digregorio presented with many of the hallmarks of ALS, also known as Lou Gehrig's disease, including signs of lower and upper motor neuron degeneration along with the absence of electrophysiological, pathological, and neuroimaging evidence of other disease processes that might explain her condition. “What wasn't fitting, of course, was age,” said Dr. Carsten Bönnemann, senior investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study. The typical age of onset for ALS is between 50 and 60-years of age. Digregorio was just 15 years old. Her symptoms began when she was around four years old with an abnormal gait and progressed to the point where she required a wheelchair for movement, and a tracheostomy tube to help her breathe by the time the NIH study began. Digregorio’s condition was so dire and perplexing that it drew the attention of Pope Francis, who prayed and offered an in-person blessing for the then 15-year-old Digregorio at the Vatican. Since then, the researchers have discovered 10 other young patients with this new form of ALS, which is genetic and appears to progress over the course of a decade. This is in contrast to the usual sporadic, non-genetic type where deterioration occurs very rapidly over a few years. “Whenever you have very early onset of the disease, we can almost bet that this is genetic, that there is a single gene behind it, so that was our hypothesis,” Bönnemann said. So, the team embarked on a mission to isolate this gene, using next-generation genomic sequencing and discovered that their patients shared variations in the DNA sequence of a specific section of the SPLTC1 gene. What they found was surprising and entirely novel. "At the time, SPLTC1 was known as a disease gene, but it caused a completely different disorder, conceptually the opposite of [Digregorio’s] disease. It caused sensory neuropathy, so exactly the opposite of what we found,” Bönnemann said. In a twist of fortuitous irony, Bönnemann discovered that Dr. Teresa M. Dunn, a professor right across the street at Uniformed Services University (USU), had devoted her career to studying this very same complex. Along with Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland, they dove into the mystery, and what they found was quite surprising. The SPLTC1 gene is involved in the production of fats, called sphingolipids, which are found in large quantities in brain tissue. Together, the researchers discovered that in the case of their patients, these sphingolipids were not being properly regulated. “That's where we found the answer,” Bönnemann said. “The regular product of the enzyme was too high. There was an overproduction that couldn't be regulated.” This newly discovered mutation “takes the brake” off of an enzyme partly responsible for the production of sphingolipids. SPT is controlled by a feedback loop, which is short-circuited by this mutation, meaning that the body produces an excess of these fats. Without medical intervention, Bönnemann said that he would not expect these young patients to survive beyond their second decade. But with proper supportive care, including a breathing machine, his hope is that this could be significantly extended. And the team might be able to do one better for these kids and young adults. “As it happens, this particular gene, SPLTC1, one doesn't really need both copies of the gene to be operating at full 100%, so if you can get rid of one of them, the other one is sufficient to maintain normal activity as long as it can be regulated,” said Dr. Payam Mohassel, an NIH clinical research fellow and the study’s lead author. So, the researchers created small interfering strands of RNA, or siRNA, designed to silence the mutant SPLTC1 gene. In lab experiments on the patients’ skin cells, these siRNA probes succeeded in reducing levels of the mutant SPTLC1 RNA, thereby allowing the enzyme’s activity to be regulated again with restoration of sphingosine levels to normal. With proof-of-concept in hand, Mohassel explained that the delivery method would need to be perfected in order to take the approach further. This is where gene therapy may be able to play a role. “Another approach is to think about converting this particular silencing siRNA into, for example, an shRNA that can be delivered by a gene therapy vector such as AAV,” Mohassel said. An additional therapeutic path could be through small molecule inhibitors of SPT, but Dunn explained that it would be a fine balance. “If we knock down the enzyme activity too much, it's going to have its own set of consequences, so we can't. We have to find just the right amount of drug that would return sphingolipids to normal without reducing them to the point where you get into other trouble,” she said. Besides providing a sense of hope for children with this devastating disease, this research could offer another clue toward unlocking the mystery behind other forms of ALS. The nature of ALS is so heterogeneous, the treatment space is often compared to oncology. Current investigative therapies are tackling the disease from multiple angles, including complement inhibition (UCB), neuroprotective agents (Prilenia Therapeutics), and a co-formulation of sodium phenylbutyrate (PB) and taurursodiol aimed at addressing the toxic, unfolded proteins and mitochondrial energy crisis (Amylyx Pharmaceuticals). In a disease like ALS, any new discovery could provide a major break. “Now we can look, even in sporadic ALS, to see whether these lipids might also be a biomarker for certain forms of ALS, and whether they could play a role in the multifactorial genesis of ALS in some way, shape, or form,” Bönnemann said. In fact, in the days since this study was published, another researcher has approached the team with an ALS patient who possesses one of the mutations reported in the study, but with a later onset. Will a therapeutic approach targeting the SPLTC1 gene come in time for Claudia Digregorio and the other 10 patients? “This is a really active area of research in many different laboratories, academic and industry,” Bönnemann said. “So, once someone finds the right modification for an siRNA to effectively target neurons, that will benefit everyone, and that could be closer than you think.”

CLEVELAND, Oct. 14, 2020 /PRNewswire/ -- The Harrington Discovery Institute® at University Hospitals in Cleveland, Ohio, and its registered charity Fund for Cures UK, Ltd., together with Morgan Stanley GIFT (Global Impact Funding Trust) Cures, announced five winners in the inaugural Harrington UK Rare Disease Scholar Award competition to advance novel treatments for rare diseases. The Harrington Discovery Institute — part of The Harrington Project for Discovery & Development — was established in 2012 to accelerate promising discoveries into new medicines to address unmet patient needs. Approximately 350 million people worldwide are living with a rare disease, and half of them are children. With more than 7,000 known rare diseases, and only five percent of those having an approved treatment, rare diseases represent one of the greatest unmet needs in healthcare today. Through its UK charity, Fund for Cures UK, Harrington Discovery Institute issued a national call for proposals in January 2020 for cutting-edge research related to rare diseases, ultra-rare diseases, and rare variants of more common diseases. In addition to grant funding, the award provides dedicated drug discovery and development support from Harrington Discovery Institute's Therapeutics Development team (experienced pharma and business development professionals with a track record of bringing new drugs to market), while taking no rights to intellectual property, which is retained by the award recipient ('Harrington Scholar') and their institution. Nearly 50 applications from scientists and physicians in 17 institutions across England, Scotland and Wales were received in response to the call. The applications progressed through multiple rounds of confidential review from both academic and industry science reviewers who evaluated the projects on the likelihood to improve standard of care, be transformative, and/or result in a licensable package, among other criteria. "In eight years we have built a strong portfolio of breakthrough science throughout the US and Canada, and we are excited to extend our reach to the United Kingdom. Together with our Scholars and their institutions, we are pleased to move one step closer to changing the rare disease landscape in a meaningful way," said Jonathan S. Stamler, MD, President, Harrington Discovery Institute, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation and Professor of Medicine at University Hospitals and Case Western Reserve University. The national grant award program is part of a broader commitment to advance rare disease treatments by working collaboratively with UK institutions. In 2019, Harrington Discovery Institute and the University of Oxford announced their transatlantic partnership to establish the Oxford-Harrington Rare Disease Centre (OHC). The OHC is focused primarily on rare diseases that have a clear genetic basis, present early in life, and fit one of three research themes: neurological disorders, developmental disorders, and cancer. Harrington UK Rare Disease Scholars may have opportunity to utilize Oxford's core labs as well as the OHC Therapeutic Accelerator (planned opening in 2021) for their projects. "The Harrington model is a bold approach that de-risks clinical drug candidates and validates their commercial potential, making them attractive to for-profit funders who are able to bring them to market. This program is an extraordinary opportunity for UK researchers to help them translate scientific discoveries into medicines that improve the lives and health outcomes of those living with a rare disease," said Peter Worrall, former Chief Financial Officer at Rex Bionics plc, and member, Board of Trustees, Fund for Cures UK. Harrington Discovery Institute will raise capital to support the growth of the UK rare disease initiative through Morgan Stanley GIFT Cures, its philanthropic partnership with global financial services firm Morgan Stanley. The 2021 Harrington UK Rare Disease Scholar Award recipients, their organizations and fields of research are: Pietro Fratta, MD, PhD – University College London Gene Therapy for Kennedy's Disease, a rare neuromuscular disease Angela Russell, DPhil – University of Oxford New Drugs for the Treatment of Duchenne Muscular Dystrophy Helen Waller-Evans, DPhil – Cardiff University Novel Inhibitors to Treat Multiple Lysomal Storage Disorders, causes of widespread organ damage Wyatt Yue, PhD – University of Oxford Inhibitors of Primary Hyperoxaluria, a cause of kidney failure Haiyan Zhou, MD, PhD – University College London Novel Therapy for SPTLC1-Related Hereditary Sensory Neuropathy, a cause of shooting pain