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: 8149433
• 负责人: Charles P Venditti
• 金额: $ 117.43万
• 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/8149433
• 关键词: Disease; Investigation; methylmalonic aciduria

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.

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。我们已经开发了小鼠、蠕虫和斑马鱼的甲基丙二酸血症和相关疾病模型，并在过去的一年里专注于小鼠模型和基因治疗。这项研究的总体目标是确定患者的并发症，了解疾病病理生理学，在小鼠或其他生物体中复制这一过程，并利用综合信息指导新疗法的开发和测试，如基因、细胞和小分子疗法。我们维持一个小鼠群体，使用细胞培养设施，使用放射性和非放射性同位素进行实验来研究细胞中的代谢，构建基因治疗载体，对小鼠进行基因治疗，并使用常规分子生物学和生化研究来分析我们的实验。