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: 8349996
• 负责人: Charles P Venditti
• 金额: $ 145.21万
• 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/8349996
• 关键词: Affect; Animal Model; Animals; Biochemical; Biological; Breath Tests; Carbon; Cell Culture Techniques; Cell Therapy; Cells; Clinical; Clinical Research; Cobalamin; Databases; Development; Disease; Enrollment; Enzymes; Evaluation; Eye; Functional disorder; Future; Gene Transduction Agent; Genes; Genotype; Goals; Human; Human Subject Research; Inherited; Inpatients; Investigation; Isotopes; Knock-out; Laboratories; Legal patent; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Metabolic Diseases; Metabolism; Methylmalonyl-CoA Mutase; Modeling; Molecular; Mus; Natural History; Neuraxis; Neurologic; Organ Transplantation; Organism; Outcomes Research; Paper; Participant; Pathology; Patients; Phenotype; Process; Propionates; Prospective Studies; Publishing; Radioisotopes; Research; Skeletal Muscle; Solid; Stroke; Syndrome; Testing; Transgenic Mice; Transgenic Organisms; Translations; Transplant Recipients; Treatment outcome; United States; United States National Institutes of Health; Zebrafish; cohort; gene therapy; in vivo; insight; metabolic abnormality assessment; methylmalonic aciduria; mouse model; novel; oxidation; patient population; propionyl-coenzyme A; research study; small molecule; translational approach; viral gene delivery

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.

这项研究包括遗传性甲基丙二酸血症（MMA）和钴胺素缺乏症，包括一种新发现的甲基丙二酸和丙二酸血症。这些代谢紊乱是遗传异质性的，共同代表了有机酸代谢的一个重要子集。 我们研究遗传性甲基丙二酸和钴胺素缺乏症和相关的条件，通过翻译的方法，包括受影响的患者的临床和代谢评估和使用动物模型，以检查在实验室中的疾病。 我们已经开发了小鼠，蠕虫和斑马鱼模型的甲基丙二酸血症和相关疾病，并专注于继续发展新的小鼠模型Mut MMA，基因治疗和细胞治疗。这些努力产生了许多已发表的论文。该研究的总体目标是确定患者中观察到的并发症，了解疾病病理生理学，在小鼠或其他生物体中复制过程，并使用组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，用放射性和非放射性同位素进行实验以研究细胞中的代谢，构建基因治疗载体，对小鼠进行基因治疗，并使用分子生物学和生物化学研究来分析我们的实验。 人类受试者研究的重点是评估美国甲基丙二酸血症、钴胺素和相关代谢紊乱的自然史，以进一步了解这组患者的治疗、结局和并发症。 我们已经开发了一个用于结局研究的患者数据库，自该项目开始以来，我们的临床研究已经招募了近100名受影响的患者。我们继续研究实体器官移植对MMA的影响，描述和定义患有疾病相关性卒中的患者的神经和神经放射学综合征，并描述了患者中观察到的一系列眼部表现。参与者通常会被送往NIH临床研究中心住院3至4天，并接受广泛的代谢测试。许多患者需要对中枢神经系统进行磁共振成像和磁共振波谱分析。我们使用高场强磁体（3 Telsa）进行这些研究。基因型-表型-酶相关性正在患者人群中进行研究。 模式生物和人类调查的结合方法，允许部分缺陷的甲基丙二酸血症小鼠模型的发展，并提供了新的见解，这种疾病的病理基础。我们还使用小鼠来测试一种有效的基因治疗载体，我们相信这种载体将来可能适用于患者。 在过去的一年里，我们发表了7篇论文，并提交了一项专利申请。在接下来的一年里，我们计划继续在NIH临床中心进行自然史研究。今年将继续努力进一步开发和完善病毒基因递送和研究细胞疗法，并希望随后将其转化为患者。 新的小鼠和斑马鱼模型的甲基丙二酸血症和相关疾病也将产生和特点。