The importance of hypoxia-regulated, RPE-targeted gene therapy for choroidal neovascularization

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world for people over 60 years of age. The most severe pathological event of AMD is choroidal neovascularization (CNV), the process of new vessel formation emerging from the choroid. The new vessels extend into the normally avascular photoreceptor cell layer, where they leak fluid and cause photoreceptor cell death. CNV is thought to be initiated by hypoxia and chronic inflammation, which occur due to abnormal, age-related changes within the retinal pigmented epithelium (RPE). These events cause increased expression of the angiogenic protein vascular endothelial growth factor (VEGF) via hypoxia-inducible factor-1 (HIF-1), a transcription factor that is vital in regulation of cellular responses to hypoxic and inflammatory conditions. Increased VEGF signaling stimulates proliferation and migration of vascular endothelial cells and facilitates the neovascular process. Current treatments for neovascular AMD are expensive, short lived, require repeated intraocular injections of VEGF-blocking agents, and are typically administered after vision loss has already occurred. Hypoxia-regulated gene therapy is an alternative strategy that targets the early pathological events leading to CNV. By incorporating HIF-1 regulatory elements with an RPE-specific promoter to drive expression of a powerful endogenous anti-angiogenic protein, this new therapeutic tool offers the possibility of pathology-initiated angiostatic treatment that can be administered prior to vision loss. © 2012 Springer Science+Business Media, LLC.