Targeting Muscle Stem Cells for the Treatment of Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by insufficient expression of the Survival of Motor Neuron (SMN) protein. SMA is the most common genetic cause of infant mortality and there is currently no cure. Although SMA is primarily characterized by motor neuron death in the spinal cord and subsequent nerve degeneration and muscle atrophy, accumulating evidence suggests that SMN deficiency may directly impair skeletal muscle development and maturation. Skeletal muscle stem cells, known as satellite cells, play a critical role in postnatal muscle growth and regeneration after damage. In this dissertation, we used novel SMA mouse models and induced pluripotent stem cell (iPSC) models to demonstrate that SMN deficiency decreases satellite cell proliferation in a cell-autonomous manner, causing insufficient production of myogenic precursors to support muscle growth. In addition, we recently demonstrated that systemic administration of therapeutic agents can enhance skeletal muscle growth by proliferating endogenous satellite cells in situ. Therefore, we hypothesized that small molecule-based, satellite cell-targeted therapies could potentially ameliorate muscle-intrinsic defects in SMA. Here, we performed a phenotypic screen and discovered small molecules across distinct drug classes that stimulate wild type satellite cell proliferation in vitro. We further identified a subset of compounds capable of proliferating SMN-deficient satellite cells in vitro and in SMA mice in vivo. These enhancements in satellite cell proliferation were associated with increased muscle size and motor strength in SMA mouse models. We propose that satellite cells are an important therapeutic target for treating SMA, through correction of the satellite cell-intrinsic defect or by pharmacological stimulation of their activity to regenerate atrophic muscle. If this approach proves efficacious, small molecule-based, satellite cell-targeted therapy could provide significant benefit for many neuromuscular and muscle disorders, such as Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), acute muscle trauma, or age-related sarcopenia.