Targeting Pathogenic Fibro-Adipogenic Progenitor Cell Differentiation to Promote Muscle Repair


Pre-Clinical Research

Poster Number: 118


Genevieve Wilson, PhD, Fulcrum Therapeutics, Inc., Alexandria Taylor, PhD, Fulcrum Therapeutics, Inc., Suchi Raghunathan, PhD, Fulcrum Therapeutics, Inc., David Matson, Fulcrum Therapeutics, Inc., Ivan Efremov, PhD, Fulcrum Therapeutics, Inc., Anthony Accorsi, PhD, Fulcrum Therapeutics, Inc.

In skeletal muscle, replacement of contractile myofibers with non-contractile fibro-fatty infiltrate is a hallmark of severe muscular dystrophies. Fibro-adipogenic progenitor cells (FAPs), a group of tissue-resident mesenchymal progenitors, exist on a tight balance, acting as major promoters of muscle regeneration during acute injury but also as a major source of pathogenic muscle replacement during chronic injury due to their ability to differentiate into myofibroblasts and adipocytes. Novel studies within the muscle field have shown that chronic muscle damage and inflammation in muscular dystrophies favor the persistence of FAPs in a pathologic state, hindering regeneration and leading to muscle fibrosis, adipogenesis, and osteogenesis. Pre-clinical research has also shown that FAPs in dystrophic muscle are poised for pathogenic differentiation. Optimization of a cellular model and read-outs of fibrogenic differentiation has led to in vitro biological validation of a fibrogenic differentiation modulator. We tested compounds across varying chemotypes and putative structurally similar negative controls, to show prevention of myofibroblast differentiation via inhibition of Target A. Future work aims at in vivo validation to assess impact on muscle function and regeneration in dystrophic mouse models. This ongoing work suggests that promotion of a pro-myogenic FAP cell state represents a significant opportunity to not only modulate muscle fibrosis but promote repair in dystrophic muscle as a means to generate novel treatments targeting the muscle micro-environment to help people living with devastating muscle disorders.