The Inherited Neuropathy Consortium (INC) RDCRC- Overall

摘要 遗传性神经病联合会(INC)RDCRC是一个临床研究人员网络，致力于 开发必要的基础设施来评估可遗传外周疾病患者的治疗 神经性疾病，统称为夏科-玛丽-图斯病(CMT)。补充资金来自 肌肉营养不良协会(MDA)和Charcot Marie Tooth Association(CMTA)，我们五名患者中的两名 倡导团体(PAG)，使Inc.从6个站点扩大到20个站点。引起CMT；90的基因 可分为三大类--以遗传性脱髓鞘神经病(CMT1)为主 遗传性轴索神经病(CMT2)和隐性遗传性神经病(CMT4)。这些就是这些团体 我们所调查的精神障碍。Inc.已招募10,000名参与者加入我们的协议，其中包括5,000名参与者 将患者纳入我们的自然历史项目。我们已经开发了CMT特定的临床结果评估 (CoA)用于测量患有CMT的成人和儿童的残疾，包括功能性和患者 报告结果(PRO)。Inc.的调查人员已经确定了包括磁共振成像在内的与 我们的COA在CMT1A，这是CMT最常见的形式。Inc.调查人员刚刚被授予U01 获奖“加速CMT1A的CMT(ACTCMT)临床试验”。我们与制药公司有关系 和学术合作伙伴分享临床数据，为试验做好准备。我们有一条关键的创新之路 与FDA的会议(CPIM)。然而，我们需要完成纵向和生物标记物的研究 CMT1A和其他常见形式的CMT将真正进行临床试验，为常见和罕见的CMT做好准备。 该公司还积极参与确定CMT的新遗传原因，包括在 过去的五年。我们已经利用GWAS将SIPA1L2鉴定为CMT1A的第一个遗传修饰物，并显示 这种基因是一个潜在的治疗靶点。我们已经启动了CMT Variant浏览器，该浏览器将 CMT遗传信息的国际共享和开发的Genesis软件共享外显子组数据 在国际上。我们现在准备将这些研究扩展到表型共享和全基因组 分析。Inc.网站还允许我们直接与构成&gt；3600名参与者的 Inc.联系注册处，他们帮助我们开发了CMT健康指数，这是一种疾病负担的专业衡量标准， 在其他出版物中。我们已经开发了CMT-国际数据库(CMT-ID)，这是一组国家 来自世界各地的注册表，使用与Inc.使用的相同的CMT最小数据集。我们有 成功培训了11名年轻的研究人员，他们都获得了与CMT相关领域的教职。我们 建议通过以下方式在即将到来的RDCRN周期中扩大我们的努力：(1)确保我们的COA和 生物标记物已做好临床试验准备，(2)开发和使用INC试点/可行性核心，(3)继续 培训下一代INC调查人员，以及(4)向患者、家属和 调查人员通过Inc.网站进行调查。

Abstract The Inherited Neuropathy Consortium (INC) RDCRC is a network of clinical investigators dedicated to developing the infrastructure necessary to evaluate therapies for patients with heritable peripheral neuropathies, collectively known as Charcot-Marie-Tooth disease (CMT). Supplemental funding from the Muscular Dystrophy Association (MDA) and Charcot Marie Tooth Association (CMTA), two of our five Patient Advocacy Groups (PAGs), has allowed the INC to expand from 6 to 20 sites. The >90 genes that cause CMT can be divided into three major groups - dominantly inherited demyelinating neuropathies (CMT1), dominantly inherited axonal neuropathies (CMT2), and recessively inherited neuropathies (CMT4). These are the groups of disorders we investigate. The INC has enrolled > 10,000 participants into our protocols including > 5,000 patients into our natural history projects. We have developed CMT specific clinical outcome assessments (COA) used to measure disability in adults and children with CMT, including both functional and patient reported outcomes (PRO). INC investigators have identified biomarkers including MRI imaging that correlate with our COA in CMT1A, the most common form of CMT. INC investigators have just been awarded a U01 award to “Accelerate Clinical Trials in CMT (ACTCMT) for CMT1A. We have relationships with pharmaceutical and academic partners to share clinical data for trial readiness. We have had a Critical Path Innovation Meeting (CPIM) meeting with the FDA. However, we need to complete longitudinal and biomarker studies in CMT1A and the other common forms of CMT to be truly clinical trial ready for common and rare forms of CMT. The INC has also been actively involved in identifying novel genetic causes of CMT including 23 during the past five years. We have utilized GWAS to identify SIPA1L2 as the first genetic modifier for CMT1A and shown that this gene is a potential therapeutic target. We have initiated the CMT Variant Browser which promotes international sharing of genetic information on CMT and developed GENESIS software to share exome data internationally. We are now poised to expand these studies into phenotypic sharing and whole genome analysis. The INC Website has also allowed us to directly interact with > 3600 participants who constitute the INC Contact Registry who have helped us develop the CMT Health Index, a PRO measure of disease burden, among other publications. We have developed the CMT-International Database (CMT-ID), a group of national registries from around the world that use the same CMT Minimal Dataset that is used by the INC. We have successfully trained 11 young investigators who have all obtained faculty positions in fields related to CMT. We propose to extend and expand our efforts in the upcoming RDCRN cycle by (1) ensuring our COA and Biomarkers are clinical trial ready, (2) Developing and utilizing an INC Pilot/Feasibility Core, (3) Continuing to train the next generation of INC investigators, and (4) Providing information to patients, families and investigators through the INC Website.