Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18

The goal of these experiments was to evaluate the potential of the fibrobla st growth factor family members FGF-5 and FCF-18 to rescue photoreceptors f rom cell death in retinal degenerative disease. Two strains of transgenic r ats, expressing either a P23H or an S334ter rhodopsin mutation, were used a s model systems. The neurotrophic growth factors were delivered by subretin al injection of adeno-associated virus vectors, driving expression of the g enes with a constitutive CMV promoter. Morphological and functional analyse s were performed to determine whether FGF-5 or FGF-18 overexpression could ameliorate cell death in the retina. Immunocytochemistry was used to determ ine the cellular sites of expression of the factors and to test for up-regu lation of FGF receptors due to injection. Significant rescue from photorece ptor cell death was found after injections of vectors expressing either FGF -5 or FGF-18 in the animal models. Increased survival of photoreceptors did not produce a significant increase in electroretinographic responses, howe ver, reflecting either trauma due to the surgery or a suppression of signal ing due to expression of proteins. Three weeks after injections, both growt h factors were localized to the inner and outer segments of photoreceptors, and the receptors FGFR1 and FGFR2 were also found to be upregulated in the se regions. No visible pathological changes were seen in the FCF-5- or FGF- 18-treated eyes. These results indicate that the delivery of either FCF-5 o r FGF-18 with adenoassociated virus protects photoreceptors from apoptosis in transgenic rat models of retinitis pigmentosa and that the rescue is pro bably mediated by conventional receptor tyrosine kinase pathways in photore ceptors.