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.

这项研究涵盖了遗传性甲基甲酸酸性血症（MMA）和钴胺毒素缺乏症。这些代谢性疾病在遗传上是异质性的，统称是有机酸血症的重要子集。 我们通过翻译方法研究了遗传性甲基甲酸酸性酸性和钴瘤性缺乏症，其中包括对患者的临床和代谢评估以及使用动物模型来检查实验室中的疾病。 我们已经开发了甲基丙二酸酯血症的小鼠和蠕虫模型，并在过去一年中继续表征这两种系统。该研究的一般目标是定义患者看到的并发症，复制小鼠或其他生物体的发现，并使用合并的信息来指导新疗法的开发和测试，例如基因和干细胞疗法。我们维持小鼠菌落，使用细胞培养设施，用放射性同位素进行实验来研究细胞中的代谢，在实验室中生长小round虫，并构建基因治疗载体。 人类受试者的研究重点是评估美国甲基化酸血症的自然史，以进一步了解这一疾病的治疗，结果和并发症。 自从开始该项目以来，我们已经开发了一个用于结果研究的患者数据库，并在我们的临床研究中招募了60多名患者。我们研究了固体器官移植对MMA的影响，并描述了一种新的神经系统综合症，这些患者患有与疾病相关的中风，并描述了一系列患者的眼睛发现。通常将患者作为住院病患者进入NIH临床研究中心3至4天，并接受广泛的代谢测试。许多患者需要中枢神经系统的磁共振成像和磁共振光谱。我们使用高场强磁铁（3 telsa）进行这些研究。患者人群正在研究基因型 - 表型 - 酶相关性。 模型生物体和人类研究的结合方法使发展了甲基化酸血症的部分缺陷鼠模型，并为在这种疾病中看到的生物营养缺陷提供了新的见解。这些实验进步的细节将在明年继续研究。 在过去的一年中，我们已经扩展了有关甲基氨基甲基-COA突变酶敲除小鼠模型的研究（Chandler RJ，Sloan J，Fu H，Fu H，Tsai M，Stabler S，Allen R，Kaestner R，Kaestner KH，Kazazian HH，Venditti CP（2007）甲基酸性和甲虫的代谢型杂种，米西尔米亚和人类均为甲状腺素的作用。 Genet 8:64）并在开发基因治疗方法中取得了重大进展，使用腺病毒和腺体相关病毒载体治疗Mut甲基甲基化酸血症小鼠（Chandler RJ，Venditti CP（2008）腺病毒腺病毒介导的基因递送的基因产生了一种新生的肠球含量（NeonaTal Murine Murine Murine Murine Murine Muline uneon unnal unnal unnal unnal hulyal hulyal humiAnal甲基化甲基元素）。 19：53-60）。在今年的甲基化酸血症的鼠模型中开发和测试病毒基因递送的努力也将继续进行，希望能够延伸到患者。