Antisense oligonucleotide mediated therapy of spinal muscular atrophy

Senthilkumar Sivanesan, Matthew D. Howell, Christine J. Didonato, Ravindra N. Singh*

*Corresponding author for this work

Research output: Contribution to journalReview article

29 Scopus citations

Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of survival motor neuron 1 (SMN1), an essential gene. SMN2, a nearly identical copy, can compensate for SMN1 loss if SMN2 exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of SMN exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of SMN2 exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore SMN2 exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote SMN2 exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalTranslational Neuroscience
Volume4
Issue number1
DOIs
StatePublished - Mar 2013

Keywords

  • ASO
  • Antisense oligonucleotide
  • ISS-N1
  • MOE
  • PMO
  • SMA
  • SMN
  • Splicing

ASJC Scopus subject areas

  • Neuroscience(all)

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