Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa

Academic Article


  • For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect in a mutation-independent manner thereby circumventing the mutational diversity. Separate adeno-associated virus (AAV) vectors were used to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. Viruses were subretinally coinjected into P347S mice, a model of dominant rhodopsin-linked retinitis pigmentosa. Benefit in retinal function and structure detected by electroretinography (ERG) and histology, respectively, was observed for at least 5 months. Notably, the photoreceptor cell layer, absent in 5-month-old untreated retinas, contained 3-4 layers of nuclei, whereas photoreceptor ultrastructure, assessed by transmission electron microscopy (TEM) improved significantly. The study provides compelling evidence that codelivered suppression and replacement is beneficial, representing a significant step toward the clinic. Additionally, dual-vector delivery of combined therapeutics represents an exciting approach, which is potentially applicable to other inherited disorders. © The American Society of Gene & Cell Therapy.
  • Authors

    Published In

  • Molecular Therapy  Journal
  • Digital Object Identifier (doi)

    Author List

  • Millington-Ward S; Chadderton N; O'Reilly M; Palfi A; Goldmann T; Kilty C; Humphries M; Wolfrum U; Bennett J; Humphries P
  • Start Page

  • 642
  • End Page

  • 649
  • Volume

  • 19
  • Issue

  • 4