NAMDC: Overall Research Plan

描述（由申请人提供）：作为罕见疾病临床研究网络（RDCRN）的成员，北美线粒体疾病联盟（NAMDC）建立了一个由18个临床中心组成的网络，以改善线粒体疾病的诊断，建立自然史并研究治疗。由于线粒体DNA（mtDNA）或核DNA（nDNA）中的原发性突变，线粒体疾病在临床上和遗传上是异质性的。只有通过一个联合体，与病人倡导团体密切合作。联合线粒体疾病基金会（UMDF）和肌肉营养不良协会，我们可以解决这些复杂的疾病。在美国国立卫生研究院（NIH）美国恢复和恢复法案（ARRA）拨款和两年U 54奖的支持下，NAMDC已经产生了一个强大的临床登记/临床纵向研究，有超过425名入组患者，一个生物库，一个教育和招募患者的网站，以及线粒体疾病研究诊断标准，这是额外临床研究的基础。从这个坚实的基础上，富有成效的以病人为导向的项目已经萌芽，包括3个自然史研究（线粒体神经胃肠脑肌病（MNGIE）、Alpers综合征和Pearson综合征，一项评估线粒体脑病乳酸酸中毒和中风样发作（MELAS）患者肌肉和脑中代谢物的超高场核磁共振的初步研究，以及广泛的前期工作（包括成功的FDA IND申请），为MNGIE的异基因造血干细胞移植（AHSCT）的创新适应性安全性研究奠定了基础。NAMDC培训计划旨在培训下一代临床研究者。需要额外的工作来获得投资于这个财团的劳动力的回报。在这项申请中，我们建议扩大NAMDC临床登记/纵向研究和生物储存库;应用和完善研究诊断标准;继续进行自然史研究;完成MNGIE AHSCT安全性研究;启动丙酮酸脱氢酶复合物缺乏症的自然史和高级遗传学研究;启动新的试点研究，包括MELAS瓜氨酸治疗的I期研究;继续NAMDC临床奖学金培训计划;并开发新的研究和合作路线，包括调查线粒体疾病患者中营养补充剂的使用情况，并与线粒体疾病序列数据资源（MSeqDR）联盟密切合作。

DESCRIPTION (provided by applicant): A member of the Rare Diseases Clinical Research Network (RDCRN), the North American Mitochondrial Disease Consortium (NAMDC) has established a network of 18 clinical centers to improve the diagnosis, establish the natural history, and investigate treatment of mitochondrial diseases. Mitochondrial diseases are clinically and genetically heterogeneous due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Only through a consortium, acting in close collaboration with the patient advocacy groups. United Mitochondrial Disease Foundation (UMDF) and Muscular Dystrophy Association, can we address these complex diseases. With support of an NIH American Recovery and Recovery Act (ARRA) grant and 2 years of a U54 award, NAMDC has already produced a powerful Clinical Registry/Clinical Longitudinal Study with over 425 enrolled patients, a Biorespository, a website for education and recruitment of patients, and mitochondrial disease Research Diagnostic Criteria, which are the foundation for additional clinical research studies. From this firm base, productive patient-oriented projects have already sprouted including 3 natural history studies (mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Alpers syndrome, and Pearson syndrome, a pilot study of ultra-high field nuclear magnetic resonance to assess metabolites in muscle and brain of patients with mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), as well as extensive preliminary work (including a successful FDA IND application) setting the stage for an innovative adaptive safety study of allogeneic hematopoietic stem cell transplantation (AHSCT) for MNGIE. The NAMDC training program has been established to train the next generation of clinician investigators. Additional work is required to reap the rewards of the labor invested in this consortium. In this application, we propose to expand the NAMDC Clinical Registry/Longitudinal Study and Biorepository; to apply and refine the Research Diagnostic Criteria; to continue on-going natural history studies; to complete the MNGIE AHSCT safety study; to launch a natural history and advanced genetics study of pyruvate dehydrogenase complex deficiency; to initiate new pilot studies including a phase I study of citrulline therapy fr MELAS; to continue the NAMDC clinical fellowship training program; and to develop new lines of research and collaborations including investigation of use of nutritional supplements among mitochondrial disease patients and close collaborations with the mitochondrial disease sequence data resource (MSeqDR) consortium.