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

Spinal muscular atrophy (SMA) is a motor neurone disease caused by a mutation in a gene called SMN1 that is necessary for the survival of motor neurons. Humans have a duplicate gene, SMN2, but that is barely expressed. One promising form of therapy involves increasing SMN2 expression. It has been assumed that it would be necessary to increase the expression of SMN2 in spinal cord motor neurons to achieve a therapeutic effect. Not so. In a mouse model of SMA, subcutaneous, peripheral administration of an antisense oligonucleotide that corrects a splicing defect in SMN2 is shown to provide a much more powerful therapy than direct delivery to the brain. Surprisingly, peripheral rescue is found to be essential for long-term rescue of SMA, and biomarkers suggest that the liver has an important role of the liver in SMA pathogenesis. 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 the survival motor neuron 1 (SMN1) gene1. Humans have a paralogue, SMN2, whose exon 7 is predominantly skipped2, but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1. SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles3, but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient4. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients5,6,7,8, reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model9,10. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection11,12. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate.