The Inherited Neuropathy Consortium (INC) RDCRC- Overall

摘要 遗传性神经病联盟（INC）RDCRC是一个临床研究者网络，致力于 发展必要的基础设施，以评估遗传性外周血淋巴细胞疾病患者的治疗方法。 神经病变，统称为Charcot-Marie-Tooth病（CMT）。来自联合国的补充资金 肌营养不良协会（MDA）和夏科玛丽牙协会（CMTA），我们的五个病人中的两个 倡导团体（PAG）使INC从6个地点扩大到20个地点。导致CMT的90多个基因 可分为三大类-显性遗传性脱髓鞘神经病（CMT 1），显性遗传性脱髓鞘神经病（CMT 2），显性遗传性脱髓鞘神经病（CMT 3），显性遗传性脱髓鞘神经病（CMT 4），显性遗传性脱髓鞘神经病（CMT 5），显性遗传性脱髓鞘神经病（CMT 6），显性遗传性脱髓鞘神经病（CMT 7），显性遗传性脱髓鞘神经病（CMT 遗传性轴突神经病（CMT 2）和复发性遗传性神经病（CMT 4）。这些是 我们所研究的疾病。INC已招募> 10，000名参与者参加我们的方案，其中包括> 5，000名 我们的自然历史项目。我们开发了CMT特定的临床结局评估 (COA)用于测量患有CMT的成人和儿童的残疾，包括功能和患者 报告结果（PRO）。INC研究人员已经确定了包括MRI成像在内的生物标志物， 我们的COA在CMT 1A中，CMT的最常见形式。INC调查人员刚刚被授予U 01 CMT 1A的“加速CMT临床试验”（ACTCMT）。我们和制药公司有关系 与学术合作伙伴共享临床数据，为试验做好准备。我们有一个关键路径创新 CPIM与FDA的会议。然而，我们需要完成纵向和生物标志物研究， CMT 1A和其他常见形式的CMT将真正为常见和罕见形式的CMT做好临床试验准备。 INC还积极参与确定CMT的新遗传原因，包括23个 近五年我们已经利用GWAS鉴定SIPA 1 L2作为CMT 1A的第一个遗传修饰因子，并显示 这个基因是一个潜在的治疗靶点我们已经启动了CMT变体浏览器， 国际共享CMT遗传信息，开发GENESIS软件共享外显子组数据 化国际大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网站还允许我们与超过3600名参与者直接互动， INC Contact Registry帮助我们开发了CMT健康指数，这是一种PRO疾病负担指标， 以及其他出版物。我们开发了CMT国际数据库（CMT-ID），一组国家级数据库， 来自世界各地的注册中心，使用INC使用的相同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CMT相关领域的教职。我们 我建议在即将到来的RDCRN周期中延长和扩大我们的努力，（1）确保我们的COA， 生物标志物已准备好进行临床试验，（2）开发和利用INC试点/可行性核心，（3）继续 培训下一代INC研究人员，以及（4）向患者、家属和 调查人员通过INC网站。

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.