Gene therapy for spinal muscular atrophy: hope and caution

Abstract

In the past decade major advances have been made in the treatment of spinal muscular atrophy, a devastating, progressive motor neuron disease caused by a deficiency in the SMN protein due to a mutation in the SMN1 gene. Several approaches aimed at increasing production of the SMN protein have been developed. The intrathecal antisense oligonucleotide nusinersen and an oral small molecule risdiplam (approved by the US Food and Drug Administration and the European Medicines Agency) target splicing of the paralogous gene SMN2, hence improving the production of the functional SMN protein. Onasemnogene abeparvovec is a one-time AAV-9-based gene transfer therapy, introducing a full copy of the SMN1 gene. Approval was based on data from the START study, 1 Mendell JR Al-Zaidy S Shell R et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017; 377: 1713-1722 Crossref PubMed Scopus (936) Google Scholar reporting an unprecedented survival rate at 24 month follow-up and unexpected acquisition of motor milestones in 12 patients with infantile-onset spinal muscular atrophy type 1, the most severe type of the disease, which is characterised by a poor prognosis with short life expectancy. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trialResults from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. Full-Text PDF