<i>SMN2</i> splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

TLDR

Spinal muscular atrophy results from loss of SMN1, and the paralogous SMN2 gene produces insufficient functional SMN protein due to alternative splicing, leading to progressive neuromuscular degeneration and high mortality. We identified orally available small molecules that selectively shift SMN2 splicing toward full-length mRNA, thereby increasing SMN protein production. Treatment of severe SMA Δ7 mice with these compounds raised SMN levels, improved motor function, preserved neuromuscular circuitry, extended lifespan, and suggests therapeutic potential for SMA patients.

Abstract

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.