Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy

Nucleic acid therapeutics allow sequence-based targeting of disease genes, such as the genes involved in spinal muscular atrophy (SMA) pathogenesis. SMA is a neuromuscular disorder caused by mutations in the survival motor neuron 1 gene (SMN1). All patients have at least one copy of a paralog, SMN2, but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. As a result, only 10 to 20 percent of SMN2 transcripts encode the fully functional SMN protein. Nusinersen, an FDA-approved therapeutic for SMA, is an antisense oligonucleotide (ASO) that promotes exon 7 inclusion in the SMN2 transcript. The ceiling effect associated with splice-switching approaches makes complementary therapeutic strategies necessary. Increasing the total pool of SMN2 transcripts and increasing the translational efficiency of these transcripts are strategies that can be used in combination with splice correction. I sought to determine whether the 5' untranslated region (5'UTR) of SMN2 contains an element that reduces its expression that can be targeted as a means of increasing SMN levels. I found that ASOs targeting the 5' end of SMN2 increase SMN mRNA and protein levels, and that this effect is due to ASO-mediated inhibition of SMN2 mRNA decay. Moreover, using the 5'UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. I show that the effect of this 5'UTR ASO is human-specific. These results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA.