Foundations for a Phase 1 Clinical Trial ofCell-based Therapy for Duchenne Muscular Dystrophy

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ABSTRACT The therapeutic landscape for Duchenne muscular dystrophy (DMD) has been transformed with the approval of five new compounds for this disease by the FDA since 2016. Four of the five compounds are antisense oligonucleotides that induce exon skipping of the dystrophin pre-mRNA, restoring the reading frame for specific subsets of pathogenic variants. These advances are remarkable, but much work remains to be done. Approximately two-thirds of the DMD population have pathogenic variants that are not amenable to any of the currently approved antisense oligonucleotide compounds. Though the life expectancy for DMD is longer than ever before with a multidisciplinary treatment approach, most affected individuals still lose ambulation during adolescence and have shortened life expectancies. There have been extensive investigations of cell-based therapeutic approaches over the past several decades, including some human clinical trials. Our group has pursued preclinical studies of a stem cell-based approach, which is advantageous due to the potential to replenish the muscle stem cell pool and enhance long term regeneration of damaged skeletal muscle. With recent preclinical advances by our team focusing on induced pluripotent stem cell (iPSC)-derived myogenic precursor cells, the timing is appropriate for a new set of human clinical trials, with the first study to be a Phase 1 evaluation of safety and tolerability of intramuscular injections. Based on extensive successful transplantation studies in mice, we hypothesize that iPSC-derived myogenic precursor cells will engraft in skeletal muscle without significant safety concerns. The goal of this planning grant is to prepare the final steps needed to initiate this Phase 1 clinical trial. The tasks to be completed during the course of this planning period include formation of the Study Team and commencement of regularly scheduled team meetings; composition and refinement of a clinical study protocol; composition and refinement of a single site manual of operating procedures (MOOP) that are compliant with NIAMS requirements; appointment of a data and safety monitoring board (DSMB) and establish a template for data and safety monitoring reports; submit a single site IRB protocol; develop a complete set of regulatory documents required for a new IND submission to the FDA; and preparation of a U01 proposal for the implementation of the Phase 1 clinical trial. By the end of the funding period, our goal is to have approval from the FDA and the IRB to initiate this study.