Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

SIMPLE SUMMARY: Globally, 5q spinal muscular atrophy (SMA) is one of the most common pediatric autosomal recessive neuromuscular diseases, with a prevalence of ~1–2 per 100,000 inhabitants and an incidence of ~1 per 10,000 live births, which makes it the most common cause of infant genetic mortality. It is characterized primarily by the progressive degeneration of α-motor neurons in the ventral grey horn of the spinal cord. Over the years, the development of innovative 5q SMN replacement and/or splice modulation strategies has provided therapeutic options for children diagnosed with 5q SMA, delaying the progression of 5q SMA and increasing patient survival, despite its extremely high cost. In this review, we provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan. ABSTRACT: The condition known as 5q spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. It is one of the most common pediatric recessive genetic diseases, and it represents the most common cause of hereditary infant mortality. After decades of intensive basic and clinical research efforts, and improvements in the standard of care, successful therapeutic milestones have been developed, delaying the progression of 5q SMA and increasing patient survival. At the same time, promising data from early-stage clinical trials have indicated that additional therapeutic options are likely to emerge in the near future. Here, we provide updated information on the molecular underpinnings of SMA; we also provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan.