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Investigations of Methylmalonic Acidemia and Related Disorders

甲基丙二酸血症及相关疾病的调查

基本信息

批准号：
10914590
负责人：
Charles P Venditti
金额：
$ 268万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10914590
关键词：
Adult Affect Animal Model Antibodies Area Australia Basal Ganglia Biochemistry Biological Assay Biological Markers Biological Sciences Blindness Blood donor Capsid Cardiac Cardiomyopathies Categories Child Childhood Chronic Chronic Kidney Failure Clinic Clinical Clinical Protocols Clinical Research Clinical Trials Clinical Trials Design Cobalamin Collaborations Communities Complex Data Databases Dedications Developed Countries Development Developmental Delay Disorders Diabetes Mellitus Diagnosis Disease Disease Progression Disease model Dose Early Intervention Effectiveness Employee End stage renal failure Extrahepatic Face Frequencies Functional disorder Gene Transduction Agent Genetic Genomic approach Genomic medicine Genomics Goals Government Grant Growth Immunosuppression Impairment Inborn Errors of Metabolism Industry Infant Inherited Institutional Review Boards Intervention Trial Investigation Kidney Knock-out Laboratories Legal patent Liver Liver diseases Medical Metabolic Metabolic Diseases Metabolism Methylmalonyl-CoA Mutase Modeling Morbidity - disease rate Myocardial dysfunction National Center for Advancing Translational Sciences National Heart, Lung, and Blood Institute National Institute of Dental and Craniofacial Research National Institute of Mental Health Natural History Neonatal Screening Neurologic Newborn Infant Obesity Organ Transplantation Orphan Drugs Osteoporosis Outcome Pancreas Pancreatitis Paper Pathology Pathway interactions Patients Pharmacodynamics Phase Phenotype Physiology Post-Translational Protein Processing Prognosis Proteomics Protocols documentation Publications Published Comment Publishing Rare Diseases Reporting Risk Safety Seroprevalences Stroke Study Section Symptoms Syndrome Testing Therapeutic Intervention Transgenic Mice Transplantation Treatment Protocols United States National Institutes of Health Visual impairment Vitamin B 12 Vitamin B 12 Deficiency Writing Zebrafish adeno-associated viral vector clinical care clinical center cohort gene therapy genetic approach genome editing hearing impairment improved insight invention ketotic hyperglycinemia long-term sequelae metabolomics methylmalonic aciduria methylmalonyl coA mutase deficiency microbiome mouse model novel novel therapeutics open label optimal treatments organ transplant rejection propionyl-coenzyme A screening small molecule targeted treatment translation to humans translational research program treatment effect vector

项目摘要

The disorders of propionyl-CoA and vitamin B12 (cobalamin) metabolism comprise a group of collectively common inherited enzymopathies in the organic acidemia category. Affected patients can display a wide range of symptoms and rate of disease progression, making delineating the natural history and designing clinical trials very challenging. In aggregate, the frequency of complications, their precipitants, long-term sequelae, optimal treatment regimens and effects of early intervention remain ill-defined for this large group of patients, who still face substantial disease associated morbidity and a poor prognosis for long-term survival. Because newborn screening for this group of disorders has become routine in the US, Australia, and many developed nations, there are growing cohorts of affected infants and children, who face a grim prognosis in the absence of disease-specific therapies. Liver, kidney, or combined organ transplantation, the only currently available treatment option for the more severely affected patients, ameliorates metabolic instability but does not provide a cure for methylmalonic acidemia (MMA) or propionic acidemia (PA) patients, who remain at risk for extrahepatic disease manifestations including neurological progression, vision and hearing loss, and sequelae of transplantation such as chronic immunosuppression, organ rejection and other transplant complications. Similarly, those with cobalamin C deficiency may have severe and early loss of vision despite medical management. Goal 1. The characterization of patients with MMA, PA and related disorders is accomplished via dedicated natural history studies, Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders (ClinicalTrials.gov Identifier: NCT00078078) and Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia (ClinicalTrials.gov Identifier:NCT02890342). Through these clinical protocols, we have assembled the largest single center cohorts of MMA and PA patients in the world, and continue to accumulate natural history data that will improve clinical care and help define outcomes for planned interventional trials. We continue to provide guidance to the community on diagnosis and management of MMA and related disorders. In the past year, we have submitted and received IRB approval for a new AAV8 gene therapy protocol to treat MMUT type MMA with our sponsor Selecta Biosciences : A Phase 1/2, Open-Label, Single Dose Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of SEL-302 (MMA-101 following administration of SEL-110) in Pediatric Subjects with Mut Subtype Isolated Methylmalonic Acidemia (MMA) (000957-HG); ClinicalTrials.gov Identifier: NCT05778877. We wrote a review on biomarkers in MMA (reference 1). Other active efforts include: delineation of the natural history of cobalamin A deficiency; the development of integrated clinical outcomes databases for MMA, PA, and cblC deficiency; the analysis of cardiac and neurological phenotypes in cblC deficiency (in collaboration with NHLBI and NIMH colleagues); and defining the natural history of hearing loss in MMA. Goal 2. Animal modeling and the study of post-translational modifications continued to be an areas of focus. We have provided commentary on metabolic changes in MMA (reference 2) and written a comprehensive review assessing the pathophysiology of MMA and related organic acidemias related to new post-translational modification termed methylmalonylation we previously discovered (reference 3). We continue to create and characterize knock-out and transgenic mouse models of disorders that afflict our patients, and have generated new mouse models of Pcca and Mmab deficiency for use in conditional genetic and therapy studies. We have also continued parallel efforts to model lethal metabolic disorders under study in the clinic using zebrafish, with the anticipation that the zebrafish models will be amendable to the facile testing of small molecules, possibly in a high throughput fashion. In the next year, we will continue to characterize the new animal models using genomic, proteomic and metabolomic analyses, then test new therapeutics, including AAV gene therapy, genome editing, small molecules, and microbiome manipulations. Goal 3. The development, testing and enablement of new genomic therapies for the disorders under study in the NIH clinical center continues as a dominant focus area for our section studies. We have continued to focus on gene therapy as treatment for methylmalonylcoa mutase (MMUT) deficiency, the most common and severe form of isolated MMA, propionic acidemia caused by deficiency of PCCA or PCCB, and isolated MMA caused by MMAB deficiency. Recent publications include a report demonstrating that the novel capsid AAV44.9, isolated by Dr J Chiorini of the NIDCR, is a potent vector for systemic gene therapy in MMA (reference 4). This paper additionally established that a low seroprevalence of anti-44.9 antibodies in heathy adult blood donors. We have also developed novel AAV vectors for human translation to treat MMAB deficiency, and filed a US patent, and two employee invention reports (EIR)s- one describing novel MMAB AAV vectors and the other, an MMAB AAV vector potency assay. We have also written a review on gene therapy for organic acidemias (reference 5). We continue to partner with NCATS to through the Platform Vector Gene Therapies Project (PaVeGT) where we are leading efforts to develop AAV9 gene therapy for PCCA and MMAB deficiencies and published a white paper describing our successful orphan drug and pediatric rare disease designation applications for an AAV9 gene therapy to treat PCCA type PA (reference 6). We also applied for a grant for the indication of PCCB deficiency and were selected by the Bespoke Gene Therapy Consortium for advancement to a clinical trial for PCCB-type PA. In the next year, we will continue to advance AAV gene therapy for MMUT, PCCA, MMAB, and PCCB deficiencies and move them toward the clinic with industry (MMUT, PCCB) and government (PCCA, MMAB) partners.

丙酰辅酶a和维生素B12（钴胺素）代谢紊乱包括一组共同的遗传性酶病在有机酸血症类别。受影响的患者可以表现出广泛的症状和疾病进展速度，使得描绘自然历史和设计临床试验非常具有挑战性。总的来说，对于这一大群患者来说，并发症的频率、引发因素、长期后遗症、最佳治疗方案和早期干预的效果仍然不明确，他们仍然面临着大量疾病相关的发病率和长期生存的不良预后。由于在美国、澳大利亚和许多发达国家，新生儿筛查这类疾病已成为常规，因此越来越多的受影响婴儿和儿童在缺乏疾病特异性治疗的情况下面临严峻的预后。肝、肾或联合器官移植是目前唯一可用的治疗方案，可改善代谢不稳定，但不能治愈甲基丙二酸血症（MMA）或丙酸血症（PA）患者，这些患者仍有肝外疾病表现的风险，包括神经系统进展、视力和听力丧失以及移植后遗症，如慢性免疫抑制。器官排斥和其他移植并发症。同样，那些缺乏钴胺素C的人，尽管有医学治疗，也可能出现严重的早期视力丧失。