Investigations of Methylmalonic Acidemia and Related Disorders

甲基丙二酸血症及相关疾病的调查

• 批准号: 7734890
• 负责人: Leslie Biesecker
• 金额: $ 77.1万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734890
• 关键词: Adenoviruses; Affect; Animal Model; Animals; Cells; Clinical; Clinical Research; Cobalamin; Condition; Cultured Cells; Databases; Defect; Development; Disease; Enrollment; Enzymes; Evaluation; Eye; Functional disorder; Gene Delivery; Gene Transduction Agent; Genes; Genetic; Genets; Genomics; Genotype; Goals; Human; Human Subject Research; Inherited; Inpatients; Investigation; Knock-out; Laboratories; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methylmalonyl-CoA Mutase; Modeling; Mus; Mutase; Natural History; Neonatal; Neuraxis; Neurologic; Organ Transplantation; Organism; Outcomes Research; Patients; Phenotype; Population; Prospective Studies; Radioisotopes; Range; Research; Role; Skeletal Muscle; Solid; Stroke; Syndrome; System; Testing; Transgenic Organisms; Transplant Recipients; Treatment outcome; United States; United States National Institutes of Health; Viral Vector; cohort; day; gene therapy; insight; mecarzole; metabolic abnormality assessment; methylmalonic aciduria; mouse model; novel therapeutics; research study; stem cell therapy; translational approach; viral gene delivery

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 and worm models of methylmalonic acidemia and have continued to characterized both systems in the past year. The general goal of the research is to define the complications seen in the patients, replicate the findings in mice or other organisms and use the combined information to guide the development and testing of new therapies, such as gene and stem cell therapy. We maintain a mouse colony, use cell culture facilities, perform experiments with radioactive isotopes to study metabolism in cells, grow small roundworms in the laboratory and construct gene therapy vectors. The human subject research is focused on assessing the natural history of methylmalonic acidemia in the United States to further understand the treatment, outcome and complications in this group of disorders. We have developed a patient database for outcomes research and have enrolled more than 60 affected patients in our clinical research studies since beginning this project. We have studied the effects of solid organ transplantation on MMA, delineated a new neurologic syndrome in patients who have suffered from a disease-related stroke and described a range of eye findings seen in one subset of patients. The patients 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 patients 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 bioenergic defect seen in this disorder. The details of these experimental advances will continue to be studied in the next year. In the past year, we have extended previous studies on our methylmalonyl-CoA mutase knock-out mouse model (Chandler RJ, Sloan J, Fu H, Tsai M, Stabler S, Allen R, Kaestner KH, Kazazian HH, Venditti CP (2007) Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle. BMC Med Genet 8:64) and have made major advances in developing gene therapy approaches to treat mice with mut methylmalonic acidemia using adenoviral and adenoassociated viral vectors (Chandler RJ, Venditti CP (2008) Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. Hum Gene Ther 19:53-60). Efforts to develop and test viral gene delivery in the murine models of methylmalonic acidemia will also continue this year, with hope that extension to patients will follow.

本研究包括遗传性甲基丙二酸血症（MMA）和钴胺素缺乏症。这些代谢紊乱在遗传上是异质的，它们共同代表了有机酸中毒的一个重要子集。我们研究遗传性甲基丙二酸血症和钴胺缺乏症通过翻译的方法，包括临床和受影响的患者的代谢评估和使用动物模型来检查疾病在实验室。我们已经开发了甲基丙二酸血症的小鼠和蠕虫模型，并在过去的一年中继续表征这两个系统。这项研究的总体目标是确定在患者身上看到的并发症，在小鼠或其他生物体中复制这些发现，并利用综合信息指导新疗法的开发和测试，如基因和干细胞疗法。我们维持一个小鼠群体，使用细胞培养设施，进行放射性同位素实验研究细胞代谢，在实验室培养小蛔虫，构建基因治疗载体。