We study a group of inborn errors of metabolism, the hereditary methylmalonic acidemias (MMA), disorders of intracellular cobalamin metabolism and propionic acidemia (PA), in the clinic and laboratory. Affected patients are medically fragile and suffer from multisystemic complications such as severe metabolic instability, stroke of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. Despite intensive study since the early 1960s, few patients with MMA or PA have survived into adulthood and evidence for effectiveness of current medical therapies is lacking, a fact that stands in stark contrast to the practice of screening all US newborns for these disorders. Because patients with MMA and PA display pathology that can be seen in many common conditions, such as vitamin B12 deficiency, stroke syndromes, pancreatic dysfunction, diabetes, chronic kidney disease, osteoporosis, and obesity, it is likely that the careful elucidation of patient phenotypes will provide new insights into the pathophysiology of more complex and prevalent disorders, and perhaps, suggest new pathways to target for therapeutic intervention that could affect millions of patients. The research program has three major interrelated goals. Goal 1 is to define the natural history of the conditions using clinical research; Goal 2 is to investigate the disorders in the laboratory using metabolic, genetic and genomic approaches and Goal 3 is to develop new treatments for the disorders, focusing gene therapy strategies. The clinical characterization of patients with methylmalonic acidemia (MMA) and related disorders, via a dedicated natural history study, NHGRI protocol Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders (ClinicalTrials.gov Identifier: NCT00078078) has continued. Through our clinical protocol, we have continued to accrue patients with MMA and cobalamin metabolic disorders and have evaluated > 180 affected individuals; this is the largest single center cohort of such patients in the world. Another section protocol focused on defining the effects of inborn errors of metabolism on pregnancy (Maternal Inborn Errors of Metabolism in Pregnancy: A Pregnancy Registry Protocol ClinicalTrials.gov Identifier:NCT02322177) remains active and a new endeavor to study propionic acidemia is nearly completed, with an IRB approved protocol that is ready to enroll patients in late 2016. We have continued to focus on the clinical characterization of patients to expand our understanding of the natural history of MMA and disorders of intracellular cobalamin metabolism. In collaboration with our colleagues in the NEI, we have published the largest and most comprehensive report on the ocular outcomes in cobalamin C deficiency (reference 1). We have continued to discuss our findings on the effects of medical food in the treatment of MMA (reference 2) and are working with nutritional support companies to develop new formulations for patients with MMA and PA. Other active efforts include defining the metabolic phenotype of MMA patients with stable isotopes. Translational investigations have continued to focus on experiments that use proteomic approaches to define disease mechanisms as well as the generation and characterization of animal models of MMA and cobalamin disorders. One recent paper describes a set of proteomic studies that used livers from patients with MMA who were seen in the natural history study and then donated their livers for research at the time of liver transplantation. Compared to unrelated (and unaffected) liver donors, the MMA patients displayed a pattern of proteomic perturbations that has provided new insights into disease pathophysiology and suggested new therapeutic approaches (reference 3). We continue to characterize knock-out models of MMAA deficiency, which causes a relatively common and severe form of vitamin B12 responsive MMA, and combined malonic-methylmalonic acidemia (CMAMMA) due to acyl-coA synthase family member 3 (ACSF3) deficiency. Finally, we have created the first viable mouse model of cobalamin C deficiency. In the next year, we will characterize the mutant mice with genomic, proteomic and metabolomic analyses, then test new therapeutics. We have continued to study viral gene therapy as treatment for methylmalonyl-CoA mutase (MUT) deficiency, the most common and severe form of MMA. During the previous cycle, and in collaboration with Dr Shawn Burgess of the NHGRI IRP, we had defined the genotoxicity of adeno-associated viral (AAV) gene therapy in mice. The controversy surrounding AAV and hepatocellular carcinoma (HCC) has expanded, and we have contributed an important commentary on this topic (reference 4). Our efforts to implement AAV gene therapy for MUT type MMA continue to progress. We used our large clinical cohort to survey the presence of neutralizing antibodies in patients with MUT MMA, and noted that most patients lacked antibodies against all AAV serotypes studied (reference 5). We have developed new AAV vectors, garnered intellectual property, and licensed our transgenes for commercial development. We have also created AAV gene therapies for cobalamin C deficiency and Niemann-Pick Type C (NPC) disease (with Dr William Pavan of the NHGRI), setting the stage for the development of gene therapy for several disorders within the NIH IRP. Manuscripts detailing these efforts are in preparation.
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