Timing of SMN replacement therapies in models of spinal muscular atrophy: a systematic review and meta-analysis

Background: Mutations in the Survival of Motor Neuron 1 (SMN1) gene lead to a loss of SMN protein in patients with spinal muscular atrophy (SMA). Revolutionary advances in gene therapy have led to SMN-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of SMN-replacement therapies is a critical determinant of success. Methods: We performed a systematic review and meta-analysis of all pre-clinical studies testing SMN replacement therapies in mouse models of SMA to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of an SMA mouse model, and evaluation of an SMN-targeting therapy. Exclusion criteria included; use of therapies not known to directly target SMN, genetic manipulations, and/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I2 statistic. Findings: 3,278 studies were initially identified, with 67 ultimately included. SMN-replacement therapies significantly affected survival in favour of treatment by a factor of 1.17 (95% CI 1.06-1.27, p<0.001) with high heterogeneity (I2=95%). Timing of treatment was a significant source of heterogeneity (p<0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and motor neuron counts were also positively associated with early treatment. Interpretation: Earlier delivery of SMN replacement therapies is a key determinant of treatment efficacy in SMA. Funding: Support for this study was provided by grant funding from SMA Europe and LifeArc/CSO Scotland (awards to THG). The Dataset related to an upcoming publication 'The effect of timing of SMN replacement on survival in mouse models of Spinal Muscular Atrophy: a systematic review and meta-analysis' by H. Chaytow, A. Motyl, N. Huang, G. Currie, Z. Bahor, E. Sena and T. Gillingwater