Restoration of vision in the PDE6ß-deficient dog, a large animal model of Rod-cone dystrophy

Defects in the beta subunit of rod cGMP phosphodiesterase 6 (PDE6 beta) 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 (rcd7) dog, a large animal model of naturally occurring PDE6 beta deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6 beta (n = 4) or AAV2/8RK.cpde6 beta (n = 4). In vivo and postmortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6 beta- and AAV2/8RK.cpde6 beta-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 rcd7 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 treatmen