Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of inherited retinal degeneration.
Knowledge of the mutations leading to inherited retinal degenerations provides a foundation for the development of somatic gene therapy in which potentially corrective genes are transferred to the target photoreceptor cells. Towards this end, we have evaluated the efficacy of a recombinant adeno-associated virus (AAV) vector to deliver and express the correct form of the cGMP phosphodiesterase-beta (PDE-beta) gene in the retinas of rd mice, which suffer rapid retinal degeneration due to recessive mutation in the endogenous gene. A truncated murine opsin promoter was used to drive expression of the PDE-beta cDNA. Following intraocular injection of AAV. PDE-beta, increased retinal expression of immunoreactive PDE protein was observed, including within photoreceptor cell bodies. Compared with age-matched controls, treated eyes showed increased numbers of photoreceptors and a two-fold increase in sensitivity to light as measured by in vitro electroretinography. These findings provide evidence that rescue of functional photoreceptor neurons can be achieved by somatic gene therapy.
Jomary
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British Retinitis Pigmentosa Society Laboratory, Department of Pharmacology, UMDS, Rayne Institute, St Thomas' Hospital, London, UK.
Vincent
K A
KA
Grist
J
J
Neal
M J
MJ
Jones
S E
SE
D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D004596:Electroretinography; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010786:Photoreceptor Cells / Q000473:pathology / Q000502:physiology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000628:therapy