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 w hich potentially corrective genes are transferred to the target photor eceptor cells. Towards this end, we have evaluated the efficacy of a r ecombinant 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 t o 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 photorecepto r cell bodies. Compared with age-matched controls, treated eyes showed increased numbers of photoreceptors and a twofold increase in sensiti vity to light as measured by in vitro electroretinography. These findi ngs provide evidence that rescue of functional photoreceptor neurons c an be achieved by somatic gene therapy.