This research study encompasses the hereditary methylmalonic acidemias (MMA) and cobalamin deficiency disorders, including a newly discovered form of combined methylmalonic and malonic acidemia. 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 and related conditions 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 the continued development of novel mouse models of Mut MMA, gene therapy, and cell therapy. Numerous published papers have resulted from these efforts. 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 molecular biological and biochemical studies to analyze our experiments. The human subject research is focused on assessing the natural history of methylmalonic acidemia, cobalamin and related 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 close to 100 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, we published 7 papers and filed one patent application. In the upcoming year, we plan to continue our natural history study in the NIH Clinical Center. Efforts to further develop and refine viral gene delivery and study cell therapy will continue this year, with hope that translation to patients will follow. Novel mouse and zebrafish models of methylmalonic acidemia and related disorders will also be generated and characterized.
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