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

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 () gene. All patients have at least one copy of a paralog, , but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. Approved treatment for SMA involves promoting exon 7 inclusion in the transcript or increasing the amount of full-length SMN by gene replacement with a viral vector. Increasing the pool of transcripts and increasing their translational efficiency can be used to enhance splice correction. We sought to determine whether the 5' untranslated region (5' UTR) of contains a repressive feature that can be targeted to increase SMN levels. We found that antisense oligonucleotides (ASOs) complementary to the 5' end of increase SMN mRNA and protein levels and that this effect is due to inhibition of mRNA decay. Moreover, use of the 5' UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. Our results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA.