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方法。由于线粒体 DNA (mtDNA) 或核 DNA (nDNA) 的原发突变，线粒体疾病在临床和遗传上具有异质性。只能通过一个联盟，与患者权益团体密切合作。联合线粒体疾病基金会 (UMDF) 和肌营养不良协会，我们可以解决这些复杂的疾病吗？在 NIH 美国康复与康复法案 (ARRA) 拨款和为期 2 年的 U54 奖项的支持下，NAMDC 已经制定了一项强大的临床登记/临床纵向研究，涵盖了超过 425 名入组患者、生物储存库、患者教育和招募网站以及线粒体疾病研究诊断标准，这些为其他临床研究奠定了基础。在这个坚实的基础上，富有成效的以患者为导向的项目已经萌芽，包括 3 项自然史研究（线粒体神经胃肠脑肌病 (MNGIE)、阿尔珀斯综合征和皮尔逊综合征、一项超高场核磁共振试点研究，用于评估线粒体脑病、乳酸性酸中毒和中风样发作 (MELAS) 患者肌肉和大脑中的代谢物，以及广泛的前期工作（包括成功的 FDA IND 申请）为MNGIE 的同种异体造血干细胞移植 (AHSCT) 的创新适应性安全研究已建立，以培训下一代临床研究人员。在此应用中，我们建议扩大 NAMDC 临床登记/纵向研究和生物库；以继续完成正在进行的自然历史研究； 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，包括瓜氨酸疗法 fr MELAS 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领域，包括调查线粒体疾病患者的营养补充剂的使用以及与线粒体疾病序列数据资源 (MSeqDR) 联盟的密切合作。

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.