Journal
RNA BIOLOGY
Volume 6, Issue 3, Pages 341-350Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/rna.6.3.8723
Keywords
survival motor neuron (SMN); SMN1; SMN2; alternative splicing; intron 7; exon 7; ISS-N1; GC-rich sequence; antisense oligonucleotide (ASO); 8-mer ASO; SMA
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Funding
- United States National Institutes of Health [R01NS055925, R21NS055149]
- Muscular Dystrophy Association, USA
- Salsbury Endowment at the Iowa State University
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Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Most SMA cases are associated with the low levels of SMN owing to deletion of Survival Motor Neuron 1 (SMN1). SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of SMN1 due to predominant skipping of exon 7. Hence, correction of aberrant splicing of SMN2 exon 7 holds the potential for cure of SMA. Here we report an 8-mer antisense oligonucleotide (ASO) to have a profound stimulatory response on correction of aberrant splicing of SMN2 exon 7 by binding to a unique GC-rich sequence located within intron 7 of SMN2. We confirm that the splicing-switching ability of this short ASO comes with a high degree of specificity and reduced off-target effect compared to larger ASOs targeting the same sequence. We further demonstrate that a single low nanomolar dose of this 8-mer ASO substantially increases the levels of SMN and a host of factors including Gemin 2, Gemin 8, ZPR1, hnRNP Q and Tra2-beta 1 known to be down-regulated in SMA. Our findings underscore the advantages and unmatched potential of very short ASOs in splicing modulation in vivo.
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