Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa

Nat Commun. 2021 Aug 16;12(1):4934. doi: 10.1038/s41467-021-25204-3.


Rhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a RhoP23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Genetic Therapy*
  • Genetic Vectors
  • HEK293 Cells
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • RNA / genetics*
  • RNA / metabolism
  • RNA Interference
  • RNA Splicing
  • Retina
  • Retinal Degeneration
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / therapy*
  • Rhodopsin / genetics
  • Rhodopsin / metabolism


  • MicroRNAs
  • RNA
  • Rhodopsin