Antisense oligonucleotide mediated therapy of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of <i>survival motor neuron 1</i> (<i>SMN1</i>), an essential gene. <i>SMN2</i>, a nearly identical copy, can compensate for <i>SMN1</i> loss if <i>SMN2</i> exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of <i>SMN</i> exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of <i>SMN2</i> exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore <i>SMN2</i> exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote <i>SMN2</i> exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.