We study a group of related 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, cardiomyopathy 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, cardiac dysfunction 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 translational 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, including animal modeling 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 > 190 affected individuals; this is the largest single center cohort of such patients in the world. A new endeavor to study propionic acidemia has been initiated this past year via NHGRI protocol Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia (ClinicalTrials.gov Identifier:NCT02890342). Like the methylmalonic acidemia (MMA) protocol, this clinical effort is unique in that it is the only dedicated natural history study being conducted on PA that utilizes an intensive dedicated hospital visit to perform detailed clinical phenotyping. At present, 10 patients have been evaluated and another 10 are expected before the end of 2017. We have continued to focus on the clinical characterization of patients to expand our understanding of these disorders. We have written a number of contemporary reviews (1-3) and opinions (4) on management of MMA and PA as well as chapters for the major pediatric textbooks on vitamin B12, organic acidemias, one carbon metabolism (reference 5-6) and amino acid metabolism (references 7-13). Active efforts include defining the metabolic phenotype of MMA and PA patients with stable isotopes; the construction of an integrated clinical outcomes database for MMA and PA; the analysis of cardiac phenotypes (in collaboration with NHLBI colleagues); and the identification and validation of protein biomarkers that correlate with disease severity. Translational investigations have continued to focus on experiments that use -omic approaches to define disease mechanisms as well as the generation and characterization of animal models. One recent paper (reference 14) describes a comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity. We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. We found that MUT heterozygosity might be a risk factor to develop T2D in humans. These experiments were performed in collaboration with Dr Patti from Harvard. We continue to characterize knock-out mouse models of MMAA deficiency, which causes a relatively common and severe form of vitamin B12 responsive MMA, combined malonic-methylmalonic acidemia (CMAMMA) due to acyl-coA synthase family member 3 (ACSF3) deficiency, and cobalamin C deficiency (MMACHC). In the next year, we will continue to characterize the mutant mice using genomic, proteomic and metabolomic analyses, then test new therapeutics, such as gene therapy. We have also initiated a parallel effort to model lethal metabolic disorder such as MUT MMA and cblC deficiency with zebrafish. We have continued to study gene therapy as treatment for methylmalonyl-CoA mutase (MUT) deficiency, the most common and severe form of MMA. We have written general reviews on gene therapy for inborn errors of metabolism (reference 15) and the use of genome editing in the treatment of IEMs (reference 16). In collaboration with Dr Shawn Burgess of the NHGRI IRP, we had previously 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 17). Moving forward, we plan to refine our efforts to develop an AAV vector for MUT MMA that can be safely administered to patients. As well, our efforts to implement AAV gene therapy for MUT type MMA continue to progress. We have developed new AAV vectors for MUT MMA, 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 our success in developing AAV gene therapy for NPC1 disease (reference 18) and a recent patent related to this work (reference 19) were also achieved in the last year.

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Human Genome Research
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Myles, Jennifer G; Manoli, Irini; Venditti, Charles P (2018) Effects of medical food leucine content in the management of methylmalonic and propionic acidemias. Curr Opin Clin Nutr Metab Care 21:42-48
An, Ding; Schneller, Jessica L; Frassetto, Andrea et al. (2017) Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. Cell Rep 21:3548-3558
Schneller, Jessica L; Lee, Ciaran M; Bao, Gang et al. (2017) Genome editing for inborn errors of metabolism: advancing towards the clinic. BMC Med 15:43
Chandler, Randy J; Williams, Ian M; Gibson, Alana L et al. (2017) Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1. Hum Mol Genet 26:52-64
Chandler, Randy J; Sands, Mark S; Venditti, Charles P (2017) Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models. Hum Gene Ther 28:314-322
Harrington, Elizabeth A; Sloan, Jennifer L; Manoli, Irini et al. (2016) Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia. Hum Gene Ther 27:345-53
Manoli, Irini; Myles, Jennifer G; Sloan, Jennifer L et al. (2016) A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency. Genet Med 18:396-404
Chandler, Randy J; LaFave, Matthew C; Varshney, Gaurav K et al. (2016) Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy? Mol Ther 24:198-201
Caterino, Marianna; Chandler, Randy J; Sloan, Jennifer L et al. (2016) The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers. Mol Biosyst 12:566-74
Manoli, Irini; Myles, Jennifer G; Sloan, Jennifer L et al. (2016) A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med 18:386-95

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