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Lolita Monnier, Elsa Lhériteau, Michel Weber, Guylène Le Meur, Jack-Yves Deschamps, Nathalie Provost, Lyse Libeau, Caroline Guihal, Philippe Moullier, Fabienne Rolling; AAV-mediated Gene Therapy Restores Retinal Function And Vision In The PDE6β-deficient Dog. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1901.
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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. Previous studies have tested gene replacement therapy in the rd10 mouse model of PDE6β-RP using adeno-associated virus (AAV) serotype 5 or 8 vectors expressing murine pde6β. They documented restoration of rod function and preservation of retinal morphology. The aim of our preclinical study was to test AAV-mediated gene replacement therapy in the rod-cone dysplasia type 1 (rcd1) dog, a naturally occurring large animal model of PDE6β deficiency that strongly replicates the human pathology.
We generated AAV2/5 and AAV2/8 vectors expressing canine pde6β cDNA under the control of the photoreceptor-specific rhodopsin kinase promoter. One hundred microliter of each vector was subretinally injected to one eye of four rcd1 dogs. The contralateral eye remained uninjected. Retinal morphology was assessed by fundus imaging, optical coherence tomography, histology and immunohistochemistry. Retinal function was tested on all treated dogs using bilateral electroretinography (ERG) at 1, 3, 6, 9 and 12 months after treatment. Moreover, vision was evaluated in all animals using behavioral testing under dim light conditions.
In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5hRK.cpde6β- and AAV2/8hRK.cpde6β-treated retinas. In all treated eyes, substantial rod-derived ERG signals were recorded as soon as 1 month post-injection (30% of normal eyes) and remained stable for at least 12 months (duration of the study). They were undetectable in untreated contralateral eyes. Most importantly, dim light vision was restored in all treated 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 progressive photoreceptor defects, the rcd1 dog.
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