Antisense oligonucleotides and spinal muscular atrophy: skipping along

Abstract

Antisense oligonucleotides (ASOs) can be used to alter the splicing of a gene and either restore production of a required protein or eliminate a toxic product. In this issue of Genes & Development, Hua and colleagues (pp. 1634-1644) show that ASOs directed against an intron splice silencer (ISS) in the survival motor neuron 2 (SMN2) gene alter the amount of full-length SMN transcript in the nervous system, restoring SMN to levels that could correct spinal muscular atrophy (SMA).

Figure 1.

Diagram of SMN1 and SMN2, and how splicing of the gene can be altered using ASOs. On the left side, the SMN2 (top) and SMN1 (bottom) genes are shown with the resulting transcripts. Note the C (SMN1)-to-T (SMN2) change is shown as disrupting a splice enhancer, but it may also act as a splice silencer (see the text). The SMN1 transcript binds both the splice activator ASF/SF2 (SR protein) and the hnRNPA1 protein, and the mRNA includes exon 7. SMN2 does not bind the splice activator, and hence the majority of the mRNA transcript lacks exon 7. The ISS-N1 is shown as binding hnRNPA1, a known negative regulator of splicing. (A) The SMN2 gene splicing is modified by either a synthetic ASO that allows binding of the SR protein to exon 7, or an ASO that blocks the binding of hnRNPA1 to the ISS-N1 site. (B) The ability to block the binding of a SR protein to a separate ESE in SMN1 exon7 is shown, essentially turning the SMN1 gene into a SMN2 gene.