Creatine Deficiency, X-Linked

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 .

The University of California Los Angeles (UCLA) has published a promising study that shows gene therapy may correct a rare creatine deficiency disorder that results in intellectual disabilities, issues with speech, involuntary movements and recurrent seizures. The study utilizes gene therapy to gradually correct abnormal creatine and guanidinoacetic acid (GAA) levels in mouse subjects with an extremely rare genetic disorder that affects creatine levels. The disorder, guanidinoacetate methyltransferase (GAMT) deficiency, is standardly treated with early creatine supplementation and optional investigational therapies. The disorder is named for the deficiency in a key enzyme involved in creatine synthesis, GAMT. GAMT enzymes are responsible for the methylation of GAA to synthesize creatine, which is then circulated to bodily tissues. Without a functioning creatine synthesis pathway, GAA levels can accumulate to toxic levels while the body suffers from a lack of creatine. In the study, the research team used an existing viral vector system intended for gene therapy to deliver a non-mutated GAMT gene. With this functioning gene, the mice developed normalized creatine and GAA levels by day 30. The subjects were monitored for one year to observe the effects this had on GAMT deficiency symptoms. According to the National Organization for Rare Disorders (NORD), GAMT deficiency management requires multidisciplinary medical attention. The brain needs creatine to function, so routine neurologist visits are necessary. The hereditary nature of the disorder beckons for geneticist consultation. Dieticians are required to ensure the patient intakes creatine-rich foods and supplementation. To manage muscle weakness and movement-related symptoms, physical therapists routinely work with patients with GAMT deficiency. Additional manifestation is seen through seizures, behavioral problems and intellectual or developmental difficulties. If left untreated and unmonitored, GAMT deficiency can lead to the development of kidney disease. Globally, as of 2015, only 110 patients with GAMT deficiency were reported. The low prevalence is likely due to the autosomal recessive hereditary pattern, through which a mutated, non-functional GAMT gene must be passed down from each parent. “What we’ve been able to demonstrate is that adult mice treated with this therapy now have normal cognitive activity, which was abnormal before the gene therapy,” said Gerald S. Lipshutz, M.D., study author and an affiliate of the UCLA Department of Surgery and the Intellectual and Developmental Disabilities Research Center at the Jane and Terry Semel Institute for Neuroscience and Human Behavior. “While the human brain and learning is more complex than that of the mouse, we hope that permanently lowering GAA toxin levels in the brain will lead to correction of cognitive and behavioral abnormalities for human patients.” As described by Lipshutz, the gene therapy method corrected the GAMT deficiency and allowed bodily functions to return to normal. The next steps for this investigational therapy will be to determine whether human trials are plausible, and a lower dose might be required to ensure patient safety. The findings were published in the scientific journal Molecular Therapy: Methods and Clinical Development. While this first phase of research was funded by a grant from the U.S. National Institute of Health and the Association for Creatine Deficiencies, it is unclear how additional research will be funded.

A new study in mice finds that a gene therapy appears to correct a rare creatine deficiency disorder that commonly results in intellectual disabilities, problems with speech, involuntary movements and recurrent seizures. A new study in mice finds that a gene therapy developed by a UCLA researcher appears to correct a rare creatine deficiency disorder that commonly results in intellectual disabilities, problems with speech, involuntary movements and recurrent seizures. The treatment potentially could represent an improvement upon available therapy for the inheritable disorder, known as guanidinoacetate methyltransferase deficiency (GAMT). Researchers found their gene therapy approach increased creatine in treated mice to normal levels and reduced toxic levels of guanidinoacetic acid (GAA), which is implicated in the pathology of the disease. Creatine plays an important role in regulating the body's energy, particularly in muscle and the brain. GAMT is one of several creatine deficiency disorders, and it occurs in an estimated 1 in 114,000 to 1 in 250,000 live births. The only therapy now available for GAMT patients is a dietary treatment of high-dose creatine, which frequently has limited effectiveness and leaves some patients at risk of recurrent seizures and other symptoms. The researchers altered a gene therapy viral vector system to carry a normal copy of GAMT, which was administered intravenously to mice genetically modified to have GAMT deficiency. Researchers studied the mice for one year to understand how the therapy altered their biochemistry, brain metabolism and behavior. Creatine levels and GAA levels were normalized in the blood of treated mice within 30 days. Testing during the study period found the mice had normal creatine levels in the tissues and organs studied by the researchers. GAA levels were normal in all but the kidney and brain, though GAA in the brain was reduced by approximately 60%. Behavioral testing found brain function in the treated mice was normalized compared to untreated mice. Brain metabolism was also normalized, which was not found with the currently available diet-based therapy when examined in mice. "What we've been able to demonstrate is that adult mice treated with this therapy now have normal cognitive activity, which was abnormal before the gene therapy," said the corresponding author of the study, Gerald S. Lipshutz, MD, of the UCLA Department of Surgery and the Intellectual and Developmental Disabilities Research Center at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA. "While the human brain and learning is more complex than that of the mouse, we would hope that permanently lowering GAA toxin levels in the brain will lead to correction of cognitive and behavioral abnormalities for human patients." The researchers plan to further refine their gene therapy approach with the goal of a lower dose for effective treatment, which could translate to greater safety for afflicted patients. Funding was provided by NIH grant R01NS110596, and additional funding was provided by the Association for Creatine Deficiencies.