Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model

Genes Dev. 2010 Aug 1;24(15):1634-44. doi: 10.1101/gad.1941310. Epub 2010 Jul 12.


Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in motor neurons is a promising approach to treat spinal muscular atrophy (SMA), a genetic neurodegenerative disease. Previously, we identified a potent 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes exon 7 inclusion in transgenic mouse peripheral tissues after systemic administration. Here we address its efficacy in the spinal cord--a prerequisite for disease treatment--and its ability to rescue a mild SMA mouse model that develops tail and ear necrosis, resembling the distal tissue necrosis reported in some SMA infants. Using a micro-osmotic pump, we directly infused the ASO into a lateral cerebral ventricle in adult mice expressing a human SMN2 transgene; the ASO gave a robust and long-lasting increase in SMN2 exon 7 inclusion measured at both the mRNA and protein levels in spinal cord motor neurons. A single embryonic or neonatal intracerebroventricular ASO injection strikingly rescued the tail and ear necrosis in SMA mice. We conclude that this MOE ASO is a promising drug candidate for SMA therapy, and, more generally, that ASOs can be used to efficiently redirect alternative splicing of target genes in the CNS.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation / drug effects
  • Male
  • Mice
  • Motor Neurons / drug effects*
  • Muscular Atrophy, Spinal* / physiopathology
  • Muscular Atrophy, Spinal* / therapy
  • Necrosis / drug therapy
  • Necrosis / physiopathology*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacokinetics
  • Oligonucleotides, Antisense / pharmacology*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Survival of Motor Neuron 2 Protein / genetics*
  • Survival of Motor Neuron 2 Protein / metabolism*
  • Transgenes / genetics


  • Oligonucleotides, Antisense
  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein