Long-term protection of retinal structure but not function using RAAV.CNTFin animal models of retinitis pigmentosa

The present study aimed to determine whether intravitreal administration of an adeno-associated virus (AAV) carrying ciliary neurotrophic factor (CNTF ) can achieve long-term morphological and physiological rescue of photorece ptors in animal models of retinitis pigmentosa, and whether injection of th is virus after degeneration begins is effective in protecting the remaining photoreceptors. We injected rAAV.CNTF.GFP intravitreally in early postnata l Prph2(Rd2/Rd2) (formerly rds/rds) mice and in adult P23H and S334ter rhod opsin transgenic rats. Contralateral eyes received an intravitreal injectio n of rAAV.GFP or a sham injection. We evaluated the eyes at 6 months (rats) and 8.5 to 9 months (mice) postinfection and looked for histological and e lectoretinographic (ERG) evidence of photoreceptor rescue and CNTF-GFP expr ession. Intravitreal administration of rAAV resulted in efficient transduct ion of retinal ganglion cells in the Prph2(Rd2/Rd2) retina, and ganglion, M uller, and horizontal/amacrine cells in the mutant rat retinas. Transgene e xpression localized to the retinal region closest to the injection site. We observed prominent morphological protection of photoreceptors in the eyes of all animals receiving rAAV.CNTF.GFP. We found the greatest protection in regions most distant from the CNTF-GFP-expressing cells. The Prph2(Rd2/Rd2 ) ERGS did not exhibit interocular differences. Eyes of the rat models admi nistered rAAV.CNTF.GFP had lower ERG amplitudes than those receiving rAAV.G FP. The discordance of functional and structural results, especially in the rat models, points to the need for a greater understanding of the mechanis m of action of CNTF before human application can be considered.