This research study encompasses the hereditary methylmalonic acidemias (MMA) and cobalamin deficiency disorders. These metabolic disorders are genetically heterogeneous and collectively represent an important subset of the organic acidemias. We study the hereditary methylmalonic acidemias and cobalmin deficiency disorders via a translational approach that includes a clinical and metabolic evaluation of affected patients and the use animal models to examine the disorder in the laboratory. We have developed mouse, worm and zebrafish models of methylmalonic acidemia and related disorders and have focused on mouse models and gene therapy in the past year. The general goal of the research is to define the complications seen in the patients, understand disease pathophysiology, replicate the processes in mice or other organisms and use the combined information to guide the development and testing of new therapies, such as gene, cell and small molecule therapy. We maintain a mouse colony, use cell culture facilities, perform experiments with radioactive and non-radioactive isotopes to study metabolism in cells, construct gene therapy vectors, administer gene therapy treatments to mice and use routine molecular biological and biochemical studies to analyze our experiments. The human subject research is focused on assessing the natural history of methylmalonic acidemia and cobalamin metabolic disorders in the United States to further understand the treatment, outcome and complications in this group of patients. We have developed a patient database for outcomes research and have enrolled more than 90 affected patients in our clinical research studies since beginning this project. We continue to study the effects of solid organ transplantation on MMA, delineate and define neurologic and neuroradiographic syndromes in patients who have suffered from a disease-related stroke and described a range of eye findings seen in the patients. Participants are usually admitted to the NIH Clinical Research Center as inpatients for 3 to 4 days and undergo extensive metabolic testing. Many patients need magnetic resonance imaging and magnetic resonance spectroscopy of the central nervous system. We use a high field strength magnet (3 Telsa) for these studies. Genotype-phenotype-enzymatic correlations are under investigation in the patient population. The combined approach of model organism and human investigations has allowed the development of a partial deficiency murine model of methylmalonic acidemia and provided new insights into the pathology underlying this disorder. We have also used mice to test an effective gene therapy vector that we believe may be applicable for patients in the future. In the past year, three major research papers have appeared describing our results. We also filed a US patent on a device and method used to track gene therapy using stable isotopes and breath testing in mice. Efforts to further develop and test viral gene delivery and cell therapy approaches in the murine models of methylmalonic acidemia will also continue this year, with hope that translation to patients will follow. Novel mouse models of methylmalonic acidemia will also be generated and studied.

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National Human Genome Research Institute
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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
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
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 1: isolated methylmalonic acidemias. Genet Med 18:386-95
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
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
Lerin, Carles; Goldfine, Allison B; Boes, Tanner et al. (2016) Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab 5:926-36
Brooks, Brian P; Thompson, Amy H; Sloan, Jennifer L et al. (2016) Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency. Ophthalmology 123:571-82

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