Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model

摘要: Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in survival 1 (SMN1) gene. Humans have paralogue, SMN2, whose exon 7 predominantly skipped, but limited amount functional, full-length SMN protein expressed SMN2 cannot fully compensate for lack SMN1. important biogenesis spliceosomal small nuclear ribonucleoprotein particles, downstream splicing targets involved pathogenesis remain elusive. There no effective SMA treatment, restoration spinal cord neurons thought to be necessary sufficient. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported severe mouse models patients, reflecting autonomic dysfunction or direct effects cardiac tissues. Here we compared systemic versus CNS model. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects restores expression after intracerebroventricular injection. Systemic administration ASO-10-27 neonates robustly rescued mice, much more than administration; subcutaneous injections extended median lifespan by 25 fold. Furthermore, neonatal mice had decreased hepatic Igfals expression, pronounced reduction circulating insulin-like growth factor (IGF1), treatment restored IGF1 normal levels. These suggest liver pathogenesis, underscoring importance peripheral tissues, demonstrate efficacy promising drug candidate.