Investigations of Methylmalonic Acidemia and Related Disorders

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

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 cohort 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. In this past year, we developed and tested a non-invasive isotopic testing method to measure hepatic propionate oxidative capacity (references 1,2), a technique we will further implement to assess the efficacy of new genomic therapy for MMA and PA. We also published an important and novel study that used machine learning and artificial intelligence to identify predictive biomarkers in patients with PA (reference 3), and continue to contribute case reports that help with management (reference 4). Our previous studies using high-dose hydroxocobalamin to treat patients with cobalamin C (cblC) deficiency will be extended to a treatment trial. Other active and planned efforts include: the construction of integrated clinical outcomes databases for MMA, PA, and cblC deficiency; the analysis of cardiac phenotypes in cblC deficiency (in collaboration with NHLBI colleagues); the delineation of the natural history of hearing loss in MMA; and the continued identification and validation of biomarkers that correlate with disease severity in MMA, PA and cblC deficiency. Goal 2. Animal modeling continues to be an area of focus. We used genome editing to study the loss of mmachc function and to develop the first viable mouse model of cblC deficiency. This new mouse model recapitulates several of the phenotypic and biochemical features of the human disorder, and shows a response to established treatments, such as hydroxocobalamin and methylcobalamin injections, as well as new therapies, such as AAV gene therapy. The NHGRI/NIH has filed a patent to protect our new treatment for cblC deficiency (Venditti CP, Sloan JL, and Manoli I. High Concentration Methylcobalamin or Combination of Methyl- And Hydroxocobalamin for the Treatment of Cobalamin C Deficiency and Related Disorders U.S. Provisional No: 63/093,084, filed October 16, 2020). A manuscript describing our new mouse models is in preparation. 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 genetics and therapy studies. We have also initiated a parallel effort to model lethal metabolic disorders such as MMUT MMA and propionic acidemia in 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, such as mRNA therapy, 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 by the section continues as a dominant focus area for our section studies. We have continued to focus on gene therapy as treatment for methylmalonyl-CoA mutase (MMUT) deficiency, the most common and severe form of isolated MMA. Recent publications include a report demonstrating that nuclease-free, AAV-mediated genome editing can provide a new treatment for MMUT deficiency (reference 5) and a paper presenting a new CNS-targeted AAV gene therapy approach that could protect the basal ganglia in MMA patients from injury (reference 6). We have also developed next generation AAV vectors for human translation, and a patent has been filed to protect these inventions (Venditti CP and Chandler RJ. Novel Adeno-Associated Viral (AAV) Vectors to Treat Hereditary Methylmalonic Acidemia (MMA) Caused by Methylmalonyl-Coa Mutase (MMUT) Deficiency, U.S. Patent Application No. U.S. Patent Application No. 63/080,337, filed September 18, 2020). An additional advance for MMA and PA gene therapy has been through participation in the NCATS led Platform Vector Gene Therapies Project ( PaVeGT) where we are leading efforts to develop AAV9 gene therapy for PCCA and MMAB deficiencies ( reference 7). We also continue to provide guidance about AAV and safety to the gene therapy community (reference 8), to study AAV integration (references 9 and 10), and to collaborate with NHGRI colleagues to develop AAV gene therapy for other applications (reference 11). In the next year, we will refine AAV gene therapy for MMUT, PCCA, and MMAB deficiencies and move them toward the clinic with industry and government (NCATS) and partners.