AAV5-mediated sFLT01 gene therapy arrests retinal lesions in Ccl2−/−/Cx3cr1−/− mice

To test the effects of adeno-associated virus encoding sFLT01 (AAV5.sFLT01) on the retinal lesions in Ccl2−/−/Cx3cr1−/− mice, a model for age-related macular degeneration (AMD), AAV5.sFLT01 was injected into the subretinal space of the right eyes and the left eyes served as controls. Histology found no retinal toxicity due to the treatment after 3 months. The treated eyes showed lesion arrest compared with lesion progression in the left eyes by fundus monitoring monthly and histological evaluation 3 months after treatment. Retinal ultrastructure showed fewer lipofuscin and better preserved photoreceptors after the treatment. A2E, a major component of lipofuscin, was lower in the treated eyes than in the control eyes. Molecular analysis showed that AAV5.sFLT01 lowered retinal extracellular signal-regulated kinase (ERK) phosphorylation and inducible nitric oxide synthetase expression, which suggested the involvement of reactive nitrogen species in the retinal lesions of Ccl2−/−/Cx3cr1−/−. We concluded that local delivery of AAV5.sFLT01 can stabilize retinal lesions in Ccl2−/−/Cx3cr1−/− mice. The findings provide further support for the potential beneficial effects of sFLT01 gene therapy for age-related macular degeneration.