Clinical Trial Readiness for Children 0-5 years with Congenital Muscular Dystrophy Secondary to LAMA2 Mutations

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This proposal’s overall goal is to hasten drug development for children < 5 years with congenital muscular dystrophy secondary to laminin α2-related dystrophies (LAMA2-RD) mutations. Excellent mouse models of differing severity improved the understanding of pathogenesis in LAMA2-RD. Therapeutic strategies, including protein replacement and apoptosis inhibition (Phase 1), linker gene transfer, and compensatory gene upregulation (pre- clinical proof of concept), are all at various developmental stages but are expected to come to clinical trials in 2-3 years. While all these advances are promising, currently, no validated clinical outcome assessments (COA) are available for children with LAMA2-RD < 5 years. Thus, the need to validate outcome measures and biomarkers is urgent for children (< 5 years) with genetically confirmed LAMA2-RD. Successfully translating any therapy must include these youngest children for whom strength or function-based approaches designed for older “cooperative children” do not work. Clinical trial readiness for infants and young children is particularly critical since therapeutic interventions, if successful, are likely to have the best response when given early. The specific aims of our proposal are to 1) Validate motor function as COA for children with LAMA2-RD, 2) Establish minimal clinically important differences for motor COAs by anchoring them to the clinical global impressions scale, 3) Determine what cohort characteristics will best inform clinical trial eligibility, and 4) Validate novel biomarkers (cross-sectionally measure biceps and rectos femoris by ultrasound) and creatine kinase levels over time. To achieve these aims, we propose a 14-site multicenter prospective 2-year study of 44 children < 5 years at enrollment. Detailed training of at least two clinical evaluators from each collaborating site will take place at the lead institution, Nationwide Children’s Hospital, before enrollment and again in Year 3. We selected the sites based on their expertise in pediatric neuromuscular clinical trials. LAMA2-RD is ultra-rare, and these children are often medically fragile. Therefore, we also selected geographically diverse locations to minimize travel and burden of trial participation. A novel COA developed by necessity during the COVID-19 Pandemic is video assessments of all motor function COAs, further allowing less travel for children. Our partnerships with advocacy groups, including Cure CMD (Congenital Muscular Dystrophy) and the Muscular Dystrophy Association, will allow us to successfully recruit children using a spoke and hub model. The proposal will develop and validate COAs for children < 5 years with LAMA2-RD and will inform future clinical trial design and interpretation. Furthermore, once validated, these COAs are very likely to be successful for children with other rare disorders affecting motor development in early infancy.