Investigations of Methylmalonic Acidemia and Related Disorders

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Disorders of propionyl-CoA and vitamin B12 (cobalamin) metabolism, including methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC), are among the more common inherited organic acidemias. These conditions are chronic, debilitating, and life-threatening diseases that present in infancy or early childhood and progress with multisystem involvement despite maximal supportive care. Patients suffer from recurrent metabolic crises, growth failure, developmental delay, progressive neurological dysfunction, cardiomyopathy, renal failure, vision loss, and in aggregate, experience a low quality of life, and heavily utilize health care resources. Although newborn screening programs now identify MMA and PA in the US and many developed nations, these patients continue to experience substantial morbidity, frequent hospitalizations, and poor long-term survival. Even with optimal medical therapy, including protein restriction, carnitine supplementation, and ammonia metabolic support, patients are at risk for metabolic decompensation and cumulative irreversible organ damage. Orthotopic liver or combined liver–kidney transplantation can improve metabolic stability and survival but does not prevent disease progression, particularly neurological and ocular manifestations, nor does it cure the underlying enzymatic defect. In cobalamin C (cblC) deficiency, for example, severe maculopathy and progressive vision loss remain refractory to current treatment. Goal 1: Natural History and Biomarkers Through NIH intramural protocols, including Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders (NCT00078078) and Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia (NCT02890342), we have assembled the world’s largest single-center MMA and PA cohorts. These studies provide unprecedented longitudinal insights into disease progression, complications, and survival, forming the foundation for trial readiness and biomarker development. Recent work demonstrates the promise of non-invasive biomarkers. Using thermal desorption–gas chromatography–mass spectrometry, we identified volatile organic compounds (VOCs) in breath that correlate with metabolic status in PA patients (reference 1). Notably, 3-pentanone was elevated 45-fold in PA patients compared to controls and associated with both biochemical derangements and neurocognitive outcomes, with levels improving post-liver transplant. Such markers may offer real-time, non-invasive disease monitoring in clinical trials. We continue to produce important reference materials for the field, and have contributed to major reference textbooks in pediatrics (reference 2) and neurology (reference 3) to review vitamin B12 and folic acid metabolism. Active efforts include delineation of the natural history of MMAA 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: Mechanistic Insights and Animal Models Mechanistic studies continue to illuminate disease pathophysiology and therapeutic targets. Using zebrafish models of PA and MMA, we discovered that proximal inhibition of branched-chain amino acid oxidation improves survival and decreases toxic metabolite accumulation, supporting novel therapeutic approaches (reference 4). We have confirmed that a new post-translational modification termed methylmalonylation can be detected in circulating biomarkers and have filed an EIR and patent in support of this novel observation (reference 5). 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, Pccb, and Mmab deficiency for use in conditional genetic and therapy studies. We have filed an EIR to report a novel model of MMAB deficiency (E-004-2025, MmabΔ3-7/Δ3-7 mouse model of metabolism of cobalamin associated B (MMAB) for the study of methylmalonic acidemia (MMA), Venditti CP and Choi EY). In the next year, we will continue to characterize the new animal models using systematic multi-omic profiling, then test new therapeutics, including AAV gene therapy, genome editing, nucleic acid therapy, small molecules, and microbiome manipulations. Goal 3: Translational Genomic Therapies 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. With NCATS, 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. We have reported, as a resource for the field, FDA interactions surrounding AAV9 gene therapy for propionic acidemia (reference 6). To pave the way for PaVe-GT's first investigational AAV gene therapy lead candidate, AAV9-hPCCA, we sought early feedback from the FDA utilizing an INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meeting. Our white paper (reference 6) elaborates on the value of establishing a TPP and the FDA INTERACT meeting by including our initial AAV9-hPCCA TPP, detailing our INTERACT meeting experience, providing all corresponding regulatory documentation, and highlighting lessons learned. The regulatory documents along with templates developed by our program can also be found on the PaVe-GT website (https://pave-gt.ncats.nih.gov/). This paper and supporting materials provide stakeholders with critical resources that can be widely applied to drug development programs in establishing a viable regulatory path to clinical trial initiation. With NCATS, we are planning an AAV8 gene therapy trial for MMUT MMA, with similar trials to follow for PCCA, MMAB, and then PCCB deficiencies. We have filed an invention report and patent on improved adeno associated viral (AAV) vectors for treatment of propionic acidemia (PA) caused by mutations in propionyl-coA carboxylase beta (PCCB) (reference 7). As part of a collaboration with Dr Porters group (NICHD), we have helped further AAV9 gene therapy for NPC1 deficiency by studying neutralizing antibody profiles in the patients (reference 8). In collaboration with Dr Ellen Sidransky’s group, we have initiated a successful AAV gene therapy program for GBA1 deficiency and filed an EIR and patent on new genes and vectors to treat GBA1 deficiency (reference 9). In collaboration with Dr Peter McGuire’s group, we have initiated a successful AAV gene therapy program for NDUSF4 deficiency and filed an EIR and patent on new genes and vectors to treat Leigh syndrome caused by NDUSF4 deficiency (reference 10). In the next year, we will continue to advance AAV gene therapy for MMUT, PCCA, MMAB, and PCCB deficiencies, move them toward the clinic with and government partnerships, and assist collaborators develop AAV gene therapy programs in the IRP. MMA, PA, and cblC deficiency are chronic, relentlessly progressive diseases that remain among the most challenging inborn errors of metabolism. Despite advances in supportive care and transplantation, patients continue to face lifelong disability, frequent hospitalizations, and shortened life expectancy. By defining natural history, discovering novel biomarkers such as 3-pentanone and methylmalonylation, developing advanced animal models, and driving translational genomics through PaVe-GT and beyond, our integrated program is laying the foundation for disease-modifying therapies that aim not only to stabilize but to cure these devastating disorders.