Ten years of disease-modifying therapy in spinal muscular atrophy: lessons learned and future directions.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by deletions or mutations in the SMN1 gene, leading to loss of motor neurons with subsequent muscle atrophy and weakness. The disease is characterized by progression in weakness and loss of function that is only partially reduced by improved standards of care. The advent of three new therapies has dramatically changed the natural history of all SMA subtypes, including the severe and advanced type I SMA. As the first drug was approved in 2016, these therapies have been available for a decade, with a rapidly increasing collection of data demonstrating their safety and efficacy in a range of clinical trials and in the real-world setting. We critically review how the field has evolved in response to the new therapies, the long-term follow-up and the emergence of new phenotypes, and the outcome of initiating these therapies in presymptomatic individuals identified via newborn screening programmes. We also review the challenges related to the interpretation of long-term outcomes once placebo-control data end, as well as the difficulties in making decisions and interpreting the results of sequential and combinatorial therapies. Finally, we review the evolution of the existing therapies, such as intrathecal gene therapy instead of its intravenous administration, or the higher dose intrathecal antisense oligonucleotide nusinersen, and new therapeutic approaches currently being studied in clinical trials.