Spinal muscular atrophy: Biology, pathogenesis, and therapeutic advances

Recently instituted world-wide newborn screening programs for spinal muscular atrophy (SMA) permit identification of at-risk individuals prior to clinical presentation of the disease. Early intervention with one or more of the available disease-modifying therapies has dramatically changed the clinical course for individuals affected by SMA. These therapies that yield such impressive results in pediatric SMA populations frequently provide more muted responses in adolescent and adult individuals with SMA. Many treated individuals experience plateau effects and pursue combination treatments to hopefully boost functional outcomes. In addition, individuals with SMA are also now living longer and experience altered disease phenotypes and challenges, such as severe and progressive scoliosis, bulbar issues and neurocognitive issues. Thus, although recent years are marked by significant advances in our understanding of disease pathogenesis and in the development and implementation of therapies to treat SMA, there are still ongoing challenges and unmet needs that will require new and innovate solutions to more fully address the needs of individuals with SMA. In this review, we provide an overview of SMA disease, including a discussion of the many diverse primary defects that have been documented in many different tissues of individuals with SMA and models of the disease, and provide an overview of the therapeutics currently available and in development to treat SMA.