AAV vectors may be well suited for efficient long-term treatment of ocular diseases because they efficiently and stably transduce retinal pigment epithelium and photoreceptor cells following subretinal injection (93,252-257). Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases that lead to progressive reduction in visual field extent and impairment of visual acuity. The disease is triggered by mutations in various genes that cause degeneration and death of photoreceptors by apoptotic pathways (258).
Modulation of photoreceptor apoptosis may offer an effective therapeutic approach to RP. AAV vectors carrying various genes including those encoding for cilliary neurotrophic factor; fibroblast growth factors FGF-2, FGF-5, and FGF-18; and glial cell line-derived neurotrophic factor were evaluated in rodent models of RP subretinal injections. In general, these studies demonstrated long-term expression of the transgene, delayed photoreceptor degeneration, increased rod photore-ceptor survival, and functional improvement (260-263).
Other therapeutic approaches to RP are aimed at specific mutant genes. Twelve percent of Americans with the blinding disease, autosomal retinitis pigmentosa, carry an autosomal dominant P23H mutation in their rhodopsin gene, and a similar transgenic rat model of this disease is available. Delivery with an AAV vector of a ribozyme targeted at this mutation in the rodent model, protected photoreceptors from death and resulted in significantly slowing the degenerative disease for 3 months (264). Mutations in the gene Prph2, which encodes the photoreceptor-specific membrane glycoprotein periph-erin-2, cause several photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy. A common feature of these diseases is the loss of photorecep-tor function, also seen in the retinal degeneration slow (Prph2Rd2/Rd2) mouse. Subretinal injection of AAV- Prph2 in these mice gave stable restoration of photoreceptor ultrastructure and electrophysiological function correction (265).
Control of angiogenesis in the retina is essential to the preservation of vision. Ocular neovascularization (NV) is a major threat to vision and a complicating feature of many eye diseases, including proliferative diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity. Regulation of vascularization in the mature retina involves a balance between endogenous positive growth factors (e.g., vascular endothelial growth factor), and inhibition of angio-genesis [e.g., pigment epithelium-derived factor (PEDF)]. Several studies examined ocular administration of AAV vectors to mice exhibiting ischemia-induced retinal NV. Expression of antiangiogenic proteins, either PEDF or the Kringle domains 1-3 of angiostatin (K1K3), gave sustained therapeutic levels of PEDF and K1K3 in the mouse eye and significantly reduced the level of retinal NV (266,267). Expression of a soluble VEGF receptor also led to significant reduction in the number of neovascular endothelial cells and inhibited retinal NV (268,269).
Recently, efficacy of AAV-based gene therapy directed at photoreceptors and retinal pigment epithelium has been demonstrated in a canine model of Leber congenital amaurosis, a childhood blindness disease. Intraocular administration of AAV-RPE65, encoding the gene for a 65-kD membrane-associated protein involved in retinoid metabolism to RPE65_/~ dogs, resulted in partial restoration of visual function (270).
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