Investigations of Methylmalonic Acidemia and Related Disorders

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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.