Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy

Mol Ther. 2014 Feb;22(2):265-277. doi: 10.1038/mt.2013.232. Epub 2013 Oct 4.


For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Dependovirus / genetics
  • Disease Models, Animal
  • Disease Progression
  • Dogs
  • Eye Proteins / genetics*
  • Gene Expression
  • Gene Knockout Techniques
  • Gene Order
  • Gene Transfer Techniques
  • Genes, Reporter
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Green Fluorescent Proteins / genetics
  • Humans
  • Promoter Regions, Genetic
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology
  • Retinitis Pigmentosa / therapy*
  • Transduction, Genetic
  • Treatment Outcome


  • Eye Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins