Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases

Neovascular age-related macular degeneration (NVAMD) is the most prevalent choroidal vascular disease, and diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the most prevalent retinal vascular diseases. In each of these, hypoxia plays a central role by stabilizing hypoxia-inducible factor-1 which increases production of vascular endothelial growth factor (VEGF) and other hypoxia-regulated gene products. High VEGF causes excessive vascular permeability, neovascularization, and in DR and RVO, promotes closure of retinal vessels exacerbating hypoxia and creating a positive feedback loop. Hence once VEGF expression is elevated it tends to remain elevated and drives disease progression. While other hypoxia-regulated gene products also contribute to pathology in these disease processes, it is remarkable how much pathology is reversed by selective inhibition of VEGF. Clinical trials have demonstrated outstanding visual outcomes in patients with NVAMD, DR, or RVO from frequent intraocular injections of VEGF-neutralizing proteins, but for a variety of reasons injection frequency has been substantially less in clinical practice and visual outcomes are disappointing. Herein we discuss the rationale, preclinical, and early clinical results of new approaches that provide sustained suppression of VEGF. These approaches will revolutionize the management of these prevalent retinal/choroidal vascular diseases.