TSUNAMI: An antisense method to phenocopy splicing-associated diseases in animals

  • Sahashi K
  • Hua Y
  • Ling K
 et al. 
  • 41


    Mendeley users who have this article in their library.
  • 15


    Citations of this article.


Antisense oligonucleotides (ASOs) are versatile molecules that can be designed to specifically alter splicing patterns of target pre-mRNAs. Here we exploit this feature to phenocopy a genetic disease. Spinal muscular atrophy (SMA) is a motor neuron disease caused by loss-of-function mutations in the SMN1 gene. The related SMN2 gene expresses suboptimal levels of functional SMN protein due to alternative splicing that skips exon 7; correcting this defect-e.g., with ASOs-is a promising therapeutic approach. We describe the use of ASOs that exacerbate SMN2 missplicing and phenocopy SMA in a dose-dependent manner when administered to transgenic Smn(-/-) mice. Intracerebroventricular ASO injection in neonatal mice recapitulates SMA-like progressive motor dysfunction, growth impairment, and shortened life span, with α-motor neuron loss and abnormal neuromuscular junctions. These SMA-like phenotypes are prevented by a therapeutic ASO that restores correct SMN2 splicing. We uncovered starvation-induced splicing changes, particularly in SMN2, which likely accelerate disease progression. These results constitute proof of principle that ASOs designed to cause sustained splicing defects can be used to induce pathogenesis and rapidly and accurately model splicing-associated diseases in animals. This approach allows the dissection of pathogenesis mechanisms, including spatial and temporal features of disease onset and progression, as well as testing of candidate therapeutics.

Author-supplied keywords

  • Antisense oligonucleotide
  • Mouse model
  • Phenocopy
  • SMN2
  • Spinal muscular atrophy
  • Splicing modulation

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document


  • Kentaro Sahashi

  • Yimin Hua

  • Karen K Y Ling

  • Gene Hung

  • Frank Rigo

  • Guy Horev

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free