Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy

Mol Ther. 2012 Nov;20(11):2019-30. doi: 10.1038/mt.2012.134. Epub 2012 Jul 24.


Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / deficiency*
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics*
  • Dependovirus / genetics
  • Disease Models, Animal
  • Dogs
  • Electroretinography
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recovery of Function
  • Retina / metabolism
  • Retina / pathology
  • Retina / physiopathology
  • Retinal Vessels / pathology
  • Retinitis Pigmentosa / physiopathology
  • Retinitis Pigmentosa / therapy*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transgenes
  • Treatment Outcome
  • Vision, Ocular


  • RNA, Messenger
  • Cyclic Nucleotide Phosphodiesterases, Type 6