AAV-mediated liver-directed gene therapy for gyrate atrophy of the choroid and retina
This research will examine some safety issues of liver-directed gene therapy.
AAV-mediated liver-directed gene therapy for gyrate atrophy of the choroid and retina
Research Summary
Dr. Nicola Brunetti-Pierri
Telethon Institute of Genetics and Medicine in Italy
Conquering Gyrate Atrophy has awarded $50,000 to support research on safety elements of liver-directed gene therapy. They have recently shown that adeno-associated virus (AAV)-mediated liver-directed gene transfer of OAT corrects systemic ornithine increase and prevents the retinal degeneration in two independent mouse models of GACR1. As liver‐directed gene therapy by AAV vectors is showing safety and efficacy in a growing number of clinical trials3-5, GACR is an attractive disease candidate. However, previous studies were performed using the hepatocyte-specific thyroxine-binding globulin (TBG) promoter to drive OAT expression and there are concerns about expression of OAT in hepatocytes not physiologically expressing OAT (i.e., periportal hepatocytes). The goals of this research are to investigate whether ectopic expression of OAT in periportal hepatocytes results in defective ureagenesis and hyperammonemia (specific aim 1) and to investigate the efficacy of an AAV vector expressing OAT under the control of the natural OAT promoter at correction of GACR phenotype in mice (specific aim 2).
Researcher Profiles
Dr. Brunetti-Pierri is a physician-scientist whose research goals are to elucidate the pathogenetic mechanisms and to develop new and more effective therapies for genetic diseases. He has defined the clinical phenotypes and identified the molecular bases of several genetic diseases (lathosterolosis, 1q21.1 deletion and duplication syndromes, FOXG1 duplication syndrome, blepharophimosis intellectual disability syndrome [BIS]). He developed proof-of-concept data supporting the efficacy of small molecule drugs for maple syrup urine disease, pyruvate dehydrogenase deficiency, urea cycle disorders, and Myhre syndrome. He has a long-standing interest in liver-directed gene therapy for inborn errors of metabolism
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Natural History Study of Gyrate Atrophy
The goal of the Gyrate Atrophy Ocular and Systemic Study is to understand the impact of OAT mutations on plasma ornithine levels and retinal degeneration.
Open for enrollment
Research Summary
Drs. Mandeep Singh and David Valle
Wilmer Eye Institute, Johns Hopkins University
Conquering Gyrate Atrophy has provided $100,000 to support the Gyrate Atrophy Ocular and Systemic (GYROS) Study. GYROS characterizes the natural history of ornithine levels and retinal degeneration (RD) associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over 4 years. The research goal is to understand the impact of OAT mutations on plasma ornithine levels and retinal degeneration.. The Foundation Fighting Blindness Consortium study is co-chaired by Drs. Mandeep Singh and David Valle, Johns Hopkins School of Medicine.
This project is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [FAIN] totaling $1.6M with 46% funded by FDA/HHS and $1.9M and 54% funded by non-government source(s). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.
Researcher Profiles
Dr. Valle is a Professor in the Department of Genetic Medicine with secondary appointments in pediatrics, medicine and ophthalmology at Johns Hopkins School of Medicine. He is board-certified in clinical molecular genetics, clinical biochemical genetics, clinical genetics and pediatrics. He is the founding Director of the Johns Hopkins Center for Inherited Disease Research and Director of the Predoctoral Training Program in Human Genetics at Johns Hopkins. He is a member of the National Academy of Medicine and has made multiple seminal discoveries regarding gyrate atrophy (GA). He is a world leader on gyrate atrophy and was the first to show that deficiency of OAT is the causative biochemical defect in GA and the first to report causative mutations in the OAT gene. He has personally overseen the metabolic management of more than 50 patients with GA. His laboratory generated the first mouse model of GA, confirmed that it developed chorioretinal degeneration, and demonstrated that an arginine-restricted diet (ARD) could prevent disease progression. He has served as lead or co-author on many clinical publications about GA, including demonstration that an ARD is therapeutically beneficial in patients with GA. Most recently, he has become co-Chair of the GYROS natural history study with Dr. Singh and was the first to show that deficiency of OAT is the causative biochemical defect in GA and the first to report causative mutations in the OAT gene. He has personally overseen the metabolic management of more than 50 patients with GA.
Dr. Singh is an Assistant Professor of Ophthalmology and Genetics. He trained in medicine in Singapore, completed a PhD at the University of Oxford (U.K.) as a Merton College Graduate Prize Scholar, followed by clinical and surgical retina fellowships at Oxford Eye Hospital and Moorfields Eye Hospital in the U.K. He is a practicing retinal specialist and vitreoretinal surgeon at the Wilmer Eye Institute, Johns Hopkins Hospital. He directs the adult inherited retinal disease service and visual electrophysiology diagnostic laboratory at Wilmer. He co-Directs the Wilmer Genetic Eye Disease Center with Dr. Doyle and is a faculty member of the Stem Cell and Ocular Regenerative Medicine (STORM) Center. His laboratory research centers on retinal regenerative medicine, with a focus on cell and gene therapy including photoreceptor regeneration and host tissue responses. He has developed novel gene and cell therapy surgical delivery approaches that are safe for children. He is study Chair of the multicenter Gyrate Atrophy Ocular and Systemic (GYROS) study, working closely with Co-Chair Dr. David Valle. He leads several clinical trials and studies on inherited retinal diseases at Johns Hopkins and is a Hartwell Investigator.
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Gene Therapy Approach with Liver Hepatocytes
The Wilmer Eye Institute and Department of Genetics, Johns Hopkins University is researching gene therapy to slow or reverse the progression of gyrate atrophy.
Gene Therapy Approach with Liver Hepatocytes
Research Summary
Drs. Jefferson Doyle, David Valle and Mandeep Singh
Wilmer Eye Institute, Johns Hopkins University
July 2022 | $50,000
In the summer of 2022, Conquering Gyrate Atrophy awarded $50,000 to the Wilmer Eye Institute and Department of Genetics, Johns Hopkins University to support research towards developing gene therapy to slow or reverse the progression of gyrate atrophy. The research will test the possibility of halting or reversing disease progression through delivery of the correct copy of the human OAT gene to liver hepatocytes in animal models with the goal of lower circulating levels of ornithine in the blood. The efficacy of the treatment will be tested in a mouse model of gyrate atrophy, using adeno-associated virus vectors targeting the hepatocytes.
Researcher Profiles
Dr. Doyle is an Assistant Professor of Ophthalmology and Genetics. He completed medical school at Oxford and Cambridge Universities in the U.K., and a PhD in cellular and molecular medicine at Johns Hopkins. He undertook a residency in ophthalmology at Johns Hopkins’ Wilmer Eye Institute, and a fellowship in pediatric ophthalmology at Boston Children’s Hospital, Harvard Medical School. He holds faculty appointments in Wilmer, the Department of Genetic Medicine (DGM) and the Cellular and Molecular Medicine graduate training program. He is a board-certified pediatric ophthalmologist who specializes in the care of patients with genetic disorders that affect the eye, including inherited retinal dystrophies (IRDs). He is co-Director of the Wilmer Genetic Eye Disease Center (GEDI) and oversees the pediatric ERG and VEP services. His research interests include the development of novel therapeutics for genetic eye issues, including gene therapy for IRDs and monogenic high myopia.
Dr. Valle is a Professor in the Department of Genetic Medicine with secondary appointments in pediatrics, medicine and ophthalmology at Johns Hopkins School of Medicine. He is board-certified in clinical molecular genetics, clinical biochemical genetics, clinical genetics and pediatrics. He is the founding Director of the Johns Hopkins Center for Inherited Disease Research and Director of the Predoctoral Training Program in Human Genetics at Johns Hopkins. He is a member of the National Academy of Medicine and has made multiple seminal discoveries regarding gyrate atrophy (GA). He is a world leader on gyrate atrophy and was the first to show that deficiency of OAT is the causative biochemical defect in GA and the first to report causative mutations in the OAT gene. He has personally overseen the metabolic management of more than 50 patients with GA. His laboratory generated the first mouse model of GA, confirmed that it developed chorioretinal degeneration, and demonstrated that an arginine-restricted diet (ARD) could prevent disease progression. He has served as lead or co-author on many clinical publications about GA, including demonstration that an ARD is therapeutically beneficial in patients with GA. Most recently, he has become co-Chair of the GYROS natural history study with Dr. Singh and was the first to show that deficiency of OAT is the causative biochemical defect in GA and the first to report causative mutations in the OAT gene. He has personally overseen the metabolic management of more than 50 patients with GA.
Dr. Singh is an Assistant Professor of Ophthalmology and Genetics. He trained in medicine in Singapore, completed a PhD at the University of Oxford (U.K.) as a Merton College Graduate Prize Scholar, followed by clinical and surgical retina fellowships at Oxford Eye Hospital and Moorfields Eye Hospital in the U.K. He is a practicing retinal specialist and vitreoretinal surgeon at the Wilmer Eye Institute, Johns Hopkins Hospital. He directs the adult inherited retinal disease service and visual electrophysiology diagnostic laboratory at Wilmer. He co-directs the Wilmer Genetic Eye Disease Center (GEDI) with Dr. Doyle and is a faculty member of the Stem Cell and Ocular Regenerative Medicine (STORM) Center. His laboratory research centers on retinal regenerative medicine, with a focus on cell and gene therapy including photoreceptor regeneration and host tissue responses. He has developed novel gene and cell therapy surgical delivery approaches that are safe for children. He is study Chair of the multicenter Gyrate Atrophy Ocular and Systemic (GYROS) study, working closely with Co-Chair Dr. David Valle. He leads several clinical trials and studies on inherited retinal diseases at Johns Hopkins and is a Hartwell Investigator.
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Drs. J. Bennett and K. Uyhazi | University of Pennsylvania
Developing gene therapy to slow or reverse the progression of gyrate atrophy
Gene Therapy Approach with Retinal Pigmented Epithelium
Research Summary
Drs. Jean Bennett and Katherine Uyhazi Center for Advanced Retinal and Ocular Therapeutics (CAROT), University of Pennsylvania
November 2020 | $150,000
In the fall of 2020, Conquering Gyrate Atrophy awarded $100,000 to the Center for Advanced Retinal and Ocular Therapeutics (CAROT) at the University of Pennsylvania to support research towards developing gene therapy to slow and/or reverse the progression of gyrate atrophy. The research will test the possibility of halting or reversing disease progression through a one-time delivery of the correct copy of the human OAT gene to the retinal pigmented epithelium (RPE) in animal models.
In August 2021, Conquering Gyrate Atrophy awarded a grant of $50,000 for additional support for this research. On December 8, 2021, Drs. Jean Bennett and Katherine Uyhazi spoke to the gyrate atrophy community about their research on gyrate atrophy and the research trends they are seeing for inherited retinal diseases. You can watch the full recording below.
In February 2023, Conquering Gyrate Atrophy awarded a grant of $50,000 for additional support for this research.
Results
Some results were shared at the 2024 ARVO conference. Conclusions are below and see the full abstact here.
GA-iPSCs have decreased viability upon orthinine exposure compared to wildtype iPSCs, which is robustly rescued by delivery of AAV2-hOAT. Together, these data provide pre-clinical evidence for the efficacy of gene replacement therapy in an in vitro model of gyrate atrophy and support future investigations of GA-iPSC derived retinal pigment epithelial cells and in vivo models of the disease.
Researcher Profiles
Dr. Bennett is a physician-scientist with expertise in molecular biology, vector development and gene therapy translational studies. She has established a true “from bench to bedside” program, and was the scientific leader of a team that translated reversal of blindness in animal models to demonstration of efficacy and safety in children and adults. This work led to the first and only approved gene therapy for inherited disease in USA and in Europe and the first approved gene therapy product targeting a retinal disease worldwide.
Dr. Uyhazi received her B.S. from The College of New Jersey, summa cum laude, and her MD/PhD from Yale School of Medicine with her PhD in Cell Biology. She completed her residency in ophthalmology and her fellowship in retinal degenerations at the Scheie Eye Institute at the University of Pennsylvania. She is currently an Assistant Professor of Ophthalmology at Penn where she has a clinical practice for inherited retinal diseases and also runs a lab focused on developing new gene therapy and stem cell therapies for retinal diseases.
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