Accelerate Clinical Trials in CMT (ACTCMT) Study

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Charcot Marie Tooth disease (CMT) is a family of rare inherited peripheral neuropathies. CMT1A accounts for 50% of all CMT and is caused by a 1.4 mB duplication within chromosome 17 that results in the overexpression of peripheral myelin protein 22 kD (PMP22). CMT1A is characterized by progressive weakness, imbalance, sensory loss, and gait abnormalities. Multiple promising candidate therapies will be ready for human clinical trials within 3- 5 years, including antisense oligonucleotide therapy that decreases PMP22 expression and corrects the phenotype of rodent models. We in the Inherited Neuropathies Consortium Rare Disease Clinical Research Network (INC RDCRN) have defined the natural history of CMT1A, and developed clinical outcome assessments, patient reported outcomes, and a functional scale for children with CMT (CMTPedS), that shows responsiveness in CMT1A. For CMT1A trials, some critical gaps in outcome measures must be urgently filled, including a validated functional outcome measure for adults (the FDA guidance identifies function as a key clinical endpoint for drug approval), and validated, disease-progression biomarkers. This study, “Accelerate Clinical Trials in CMT (ACTCMT)”, addresses these key gaps by leveraging the expertise and multicenter infrastructure of the INC RDCRN to conduct a multicenter validation of a functional outcome (CMT-FOM), and motor and sensory biomarkers in adults with CMT1A. The aims of this U01 proposal include the following: (1) Validation of the CMT-FOM as a responsive outcome measure in adults with CMT1A. The CMT-FOM has high patient relevance, as it incorporates the patient perspective on which functional limitations are impactful. (2) Validation of a quantitative three-point Dixon MRI of intramuscular fat accumulation as a biomarker of disease progression in key leg muscles invoked in foot drop and disability for use in early phase CMT1A trials. (3) Validation of a non-invasive and painless way to determine the density of Meissner corpuscles (an important kind of sensory receptor) in the skin as a sensory biomarker for CMT1A trials. Dr. D. Herrmann (U. Rochester), will serve as overall PI. Dr. Herrmann developed CMT-FOM and will co-lead AIM 1 with Dr. M. Shy (INC Director; U. Iowa) and Dr. J. Burns (U. Sydney; who developed the CMTPedS). Dr. Herrmann pioneered the use of non-invasive imaging of Meissner corpuscles in peripheral neuropathy, and will also lead AIM 3. Dr. M. Reilly and Dr. J. Thornton (physicist), both from the Univ. College of London, will lead AIM 2; they pioneered the use of muscle MRI as a biomarker in CMT1A. Drs. S. Scherer (U. Penn) and D. Pareyson (C. Besta Neurological Inst., Milan) lead large CMT clinics and have considerable experience in evaluating CMT1A patients. This study brings together a leading group of CMT investigators who have a long history of successfully collaborating, and should yield a validated CMT-FOM and biomarkers that will have high impact because this will accelerate early and late phase clinical trials in CMT1A, for which no disease-modifying treatment is yet available.