Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy

Background Prph2(Rd2/Rd2) mice have a retinal degeneration due to a null mutation for the Prph2 gene which encodes a photoreceptor-specific glycoprotein, peripherin2, essential for outer-segment formation. We have previously shown improvement of photoreceptor function at a single time point following AAV-mediated gene replacement therapy. Here we quantify the functional rescue over a 15-week time course and present a detailed analysis of the improvement in retinal function. Methods An AAV2 vector AAV.rho.rds carrying a peripherin2 c-DNA was in injected subretinally into 10-day-old Prph2(Rd2/Rd2) mice. One group was injected at a single time point while in a second group the injections were repeated after 5 days. The effect of treatment was analysed histologically using electron microscopy and electroretinography (ERG) was used to assess functional changes. Treated mice were recorded at regular intervals over 15 weeks. Untreated contralateral eyes served as internal control. Results A significant increase in b-wave amplitude was first noted 3 weeks after treatment of 10-day-old Prph2(Rd2/Rd2) mice and persisted for up to 14 weeks. An increase in the area of retina exposed to vector resulted in a significant increase in both b-wave amplitude and persistence. Conclusions In this study AAV-mediated gene replacement in Prph2(Rd2/Rd2) mice resulted in a significant functional improvement over a period of 14 weeks. These results support the utility of gene therapy approaches as treatment for photoreceptor dystrophies. Copyright (C) 2003 John Wiley Sons, Ltd.