Intravitreal Administration of AAV2-SIRT1 Reverses Diabetic Retinopathy in a Mouse Model of Type 2 Diabetes

PURPOSE: The expression of silent information regulator (SIRT) 1 is reduced in diabetic retinopathy (DR). Previous studies showed that alterations in SIRT1 messenger RNA (mRNA) and protein expression are implicated in progressive inflammation and formation of retinal acellular capillaries. Treatment with the SIRT1 agonist, SRT1720, improved visual response by restoration of a- and b-wave responses on electroretinogram scotopic measurements in diabetic (db/db) mice. In this study, we investigated the effects of intravitreal SIRT1 delivery on diabetic retinal pathology. METHODS: Nine-month-old db/db mice received one intravitreal injection of either AAV2-SIRT1 or AAV2-GFP control virus, and after 3 months, electroretinography and optomotor responses were measured. Their eyes were then removed and analyzed by immunohistochemistry and flow cytometry. RESULTS: SIRT1 mRNA and protein levels were increased following AAV2-SIRT1 administration compared to control virus AAV2-GFP injected mice. IBA1(+) and caspase 3 expression were decreased in retinas of db/db mice injected with AAV2-SIRT1, and reductions in scotopic a- and b-waves and high spatial frequency in optokinetic response were prevented. Retinal hypoxia inducible factor 1α (HIF-1α) protein levels were reduced in the AAV2-SIRT1–injected mice compared to control-injected mice. Using flow cytometry to assess changes in intracellular HIF-1α levels, endothelial cells (CD31(+)) from AAV-2 SIRT1 injected mice demonstrated reduced HIF-1α expression compared to db/db mice injected with the control virus. CONCLUSIONS: Intravitreal AAV2-SIRT1 delivery increased retina SIRT1 and transduced neural and endothelial cells, thus reversing functional damage and improving overall visual function. TRANSLATIONAL RELEVANCE: AAV2-SIRT1 gene therapy represents a beneficial approach for the treatment of chronic retinal conditions such as DR.