Skip to main content
Article
A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy
RNA Biology
  • Natalia N. Singh, Iowa State University
  • Maria Shishimorova, Iowa State University
  • Lu Cheng Cao, University of Massachusetts Medical School Worcester
  • Laxman Gangwani, Medical College of Georgia
  • Ravindra N. Singh, Iowa State University
Document Type
Article
Publication Version
Published Version
Publication Date
1-1-2009
DOI
10.4161/rna.6.3.8723
Abstract

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-β1 known to be down regulated in SMA. Our findings underscore the advantages and unmatched potential of very short ASOs in splicing modulation in vivo.

Comments

This is an article from RNA Biology 6 (2009): 341, doi:10.4161/rna.6.3.8723. Posted with permission

Rights
This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
Copyright Owner
Landes Bioscience
Language
en
File Format
application/pdf
Citation Information
Natalia N. Singh, Maria Shishimorova, Lu Cheng Cao, Laxman Gangwani, et al.. "A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy" RNA Biology Vol. 6 Iss. 3 (2009) p. 341 - 350
Available at: http://works.bepress.com/ravindra-singh/10/