Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations

Mol Ther. 2021 Aug 4;29(8):2441-2455. doi: 10.1016/j.ymthe.2021.04.024. Epub 2021 Apr 23.


Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13. Skipping exon 13 from the USH2A transcript presents a potential treatment modality in which the resulting transcript is predicted to encode a slightly shortened usherin protein. Morpholino-induced skipping of ush2a exon 13 in zebrafish ush2armc1 mutants resulted in the production of usherinΔexon 13 protein and a completely restored retinal function. Antisense oligonucleotides were investigated for their potential to selectively induce human USH2A exon 13 skipping. Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation. Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection and induced a detectable level of exon skipping until at least 6 months post-injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13.

Keywords: USH2A; antisense oligonucleotide; exon skipping; retinitis pigmentosa; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Exons
  • Extracellular Matrix Proteins / chemistry
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • Models, Molecular
  • Mutation*
  • Oligonucleotides, Antisense / administration & dosage*
  • Oligonucleotides, Antisense / pharmacology
  • Retina / metabolism
  • Retinitis Pigmentosa / drug therapy*
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / metabolism
  • Zebrafish
  • Zebrafish Proteins / chemistry
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Extracellular Matrix Proteins
  • Oligonucleotides, Antisense
  • USH2A protein, human
  • Zebrafish Proteins