AAV - Mediated PEDF Gene Transfer Counteracts Diabetic Retinopathy In IGF-I Transgenic Mice
Abstract Number: 49-OR
Authors: PILAR VILLACAMPA, VIRGINIA HAURIGOT, ALBERT RIBERA, DAVID RAMOS, ASSUMPCIO BOSCH, JESUS RUBERTE, FATIMA BOSCH, Bellaterra (Cerdanyola del Valles), Spain
Institutions: Bellaterra (Cerdanyola del Valles), Spain
Results: Diabetic retinopathy is the leading cause of loss of visual acuity and blindness in adulthood. Transgenic mice overexpressing Insulin-like Growth Factor (IGF-I) in the retina have retinal alterations characteristic of non-proliferative retinopathy and, with age, mice develop alterations that mimic the proliferative stage of diabetic retinopathy such as neovascularization in the vitreous cavity and retinal neovascularization. Current therapeutic approaches for diabetic retinopathy, such as laser photocoagulation and vitrectomy, are invasive and merely palliative and repetitive local delivery of drugs is not desirable in a chronic disease. Therefore, it is necessary to develop new therapeutic approaches for diabetic retinopathy. Viral-vector-mediated gene transfer allows continuous local production of therapeutic proteins. In our lab, we have undertaken viral vector intravitreous delivery in mice retinas and we have expressed Green Fluorescent Protein (GFP) marker gene with adeno-associated virus (AAV) of different serotypes. Our studies show that AAV2 vectors have a high efficiency in the transduction of cells of the ganglionar layer and also cells in the inner nuclear layer. A year after a single intravitreal injection, GFP protein was still detected in mice retinas. With the aim of overcoming the angiogenic process present in the transgenic mice retina, we designed a strategy for the continuous production of the antiangiogenic factor Pigmented Epithelium Derived Factor (PEDF) using an AAV2 viral vector. PEDF is normally secreted by retinal pigmented epithelium cells and its levels are decreased in the vitreous humor of diabetic patients. PEDF is one of the most potent anti angiogenic factors and also hasneuroprotective properties, making it an excellent candidate for gene transfer in diabetic retinopathy. PEDF was detected in retinas of mice six months after intravitreal injection of AAV2 PEDF. These animals had a significant reduction of neovascularization in the retina, as measured by fluorescein angiography morphometry and also showed a decrease in retinal inflammatory molecule levels, such as Intercellular Adhesion Molecule 1 (ICAM-1).