NAMDC: Overall Research Plan

描述（由申请人提供）：北美线粒体疾病联盟（NAMDC）是罕见病临床研究网络（RDCRN）的成员，建立了一个由18个临床中心组成的网络，以提高线粒体疾病的诊断，建立自然史和研究治疗方法。由于线粒体DNA （mtDNA）或核DNA （nDNA）的原发性突变，线粒体疾病在临床上和遗传学上都是异质性的。只有通过一个联盟，与患者权益团体密切合作。联合线粒体疾病基金会（UMDF）和肌肉萎缩症协会，我们能解决这些复杂的疾病吗？在美国国立卫生研究院美国康复与恢复法案（ARRA）拨款和2年的U54奖的支持下，NAMDC已经完成了一项强大的临床注册/临床纵向研究，有超过425名注册患者，一个生物存储库，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，这是进一步临床研究的基础。在这个坚实的基础上，以患者为导向的生产性项目已经萌芽，包括3项自然史研究（线粒体神经胃肠性脑肌病（MNGIE）、Alpers综合征和Pearson综合征）、一项用于评估线粒体脑病乳酸酸中毒和卒中样发作（MELAS）患者肌肉和大脑代谢物的超强场核磁共振试点研究；以及广泛的初步工作（包括成功的FDA IND申请）为针对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培训计划的建立是为了培训下一代临床研究人员。为了获得在这个联合体中投入的劳动的回报，还需要做更多的工作。在此申请中，我们建议扩展NAMDC临床注册/纵向研究和生物库；应用及完善研究诊断准则；继续进行自然历史研究；完成MNGIE AHSCT安全性研究；开展丙酮酸脱氢酶复合物缺乏症的自然历史和高级遗传学研究；启动新的试点研究，包括瓜氨酸治疗MELAS的I期研究；继续NAMDC临床研究员培训项目；并开发新的研究和合作路线，包括线粒体疾病患者营养补充剂使用的调查，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.