NAMDC: Overall Research Plan

描述(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，以改进线粒体疾病的诊断，建立自然病史，并调查治疗方法。由于线粒体DNA(MtDNA)或核DNA(NDNA)的原始突变，线粒体疾病在临床和遗传上是不同的。仅通过一个财团，与患者权益倡导团体密切合作。联合线粒体疾病基金会(UMDF)和肌营养不良症协会，我们可以解决这些复杂的疾病。在美国国立卫生研究院美国康复法案(ARRA)的资助和两年的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，包括超过425名登记患者、一个生物资源库、一个患者教育和招募网站以及线粒体疾病研究诊断标准，这些都是其他临床研究研究的基础。在此坚实的基础上，以患者为导向的富有成效的项目已经涌现，包括3项自然病史研究(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卒中样发作(MELAS)患者肌肉和脑内代谢物的超高场核磁共振试点研究，以及广泛的前期工作(包括FDA的成功IND应用)，为异基因造血干细胞移植(AHSCT)治疗MNGIE的创新性适应性安全性研究奠定了基础。NAMDC培训计划已经建立，以培训下一代临床医生调查人员。需要额外的工作才能获得投资于该财团的劳动的回报。在这项申请中，我们提议扩大NAMDC临床注册/纵向研究和生物库；应用和完善研究诊断标准；继续进行中的自然病史研究；完成MNGIE AHSCT安全性研究；启动丙酮酸脱氢酶复合体缺乏症的自然历史和高级遗传学研究；启动新的先导性研究，包括在MELAS进行瓜氨酸疗法的第一阶段研究；继续NAMDC临床研究员培训计划；以及开发新的研究与合作路线，包括调查线粒体疾病患者使用营养补充剂的情况以及与线粒体疾病序列数据资源(MSeqDR)财团的密切合作。

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.