The Inherited Neuropathy Consortium (INC) RDCRC- Overall

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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.