Subretinal delivery of AAV5-mediated human gene ameliorates the disease phenotype in a rat model of retinitis pigmentosa.

PURPOSE

A genetic disorder that affects the beta subunit of cyclic guanosine monophosphate-phosphodiesterase type 6 (PDE6B) in humans leads to autosomal recessive retinitis pigmentosa (RP). This condition causes severe vision loss in early life due to fast deterioration of photoreceptors. This study evaluated the therapeutic potential of subretinal delivery of the adeno-associated virus (AAV)5-mediated human gene in an RP rat model caused by gene knockout (KO).

METHODS

We compared the transduction efficiency and tropism of different AAV serotypes (2, 5 and 8) in KO rats and found that AAV5 had the highest and most specific expression in photoreceptors. We injected AAV5- into the subretinal space of KO rats on postnatal day 21. We assessed the protective effects six weeks postinjection by measuring PDE6B protein expression, photoreceptor structure, retinal morphology and thickness, retinal pigment epithelium integrity and visual function.

RESULTS

AAV5- treatment ameliorated the disease phenotype in KO rats by restoring PDE6B protein expression, preserving photoreceptor structure, improving retinal morphology and thickness, and maintaining retinal pigment epithelium integrity. Functional analysis of vision by scotopic electroretinogram (ERG) and optokinetic nystagmus revealed that AAV5- treatment significantly improved the visual function of gene KO rats compared with AAV5--injected KO rats.

CONCLUSIONS

Our results demonstrate that AAV5- may be a potential therapeutic gene candidate for RP caused by mutations.