Pathological impact of SMN2 mis‐splicing in adult SMA mice

Abstract

Abstract Loss‐of‐function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult‐onset (type IV) SMA. There is currently no animal model for adult‐onset SMA, and the tissue‐specific pathogenesis of post‐developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis‐splicing. Intracerebroventricular ASO injection in adult SMN2‐transgenic mice phenocopies key aspects of adult‐onset SMA, including delayed‐onset motor dysfunction and relevant histopathological features. SMN2 mis‐splicing increases during late‐stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis‐splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose–response and time‐course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing‐correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult‐onset and early‐onset SMA.

Keywords

• adult‐onset SMA
• pathology
• SMN2
• spinal muscular atrophy
• splicing