Spinal Muscular Atrophy: In the Challenge Lies a Solution

Abstract

The path from gene discovery to therapy in spinal muscular atrophy (SMA) has been a highly challenging endeavor, but also led to one of the most successful stories in neurogenetics. In SMA, a neuromuscular disorder with an often fatal outcome until recently, with those affected never able to sit, stand, or walk, children now achieve these motoric abilities and almost age-based development when treated presymptomatically. This review summarizes the challenges along this 30-year journey. It is also meant to inspire early-career scientists not to give up when things become difficult but to try to uncover the biological underpinnings and transform the challenge into the next big discovery. Without doubt, the improvements seen with the three therapeutic strategies in SMA are impressive; many open questions remain and are discussed in this review.

Keywords: ASOs; SMA; SMN1; SMN2; gene therapy; genetic modifiers; splicing.