Beyond VEGF—The Weisenfeld Lecture

Abstract

PurposeTo review advances made in the treatment of age-related macular degeneration (AMD) and share perspectives on the future of AMD treatment.MethodsReview of published clinical and experimental studies.ResultsInhibitors of vascular endothelial growth factor (VEGF) truly revolutionized the treatment of AMD. However, available results from longer-term studies suggest that a degenerative process is unveiled, and continues to occur, even when neovascularization is controlled. Furthermore, anti-VEGF therapy may play a role in the development of atrophic changes. We have proposed using neuroprotection to prevent atrophy, and multiple models of retinal degeneration have shown that it is necessary to block both apoptotic and necrotic cell death pathways. Despite the success of anti-VEGF therapy and the promise of neuroprotection, neither addresses the underlying cause of AMD. It has been postulated that in early AMD, the retention and abnormal accumulation of lipids in Bruch's membrane and below the retinal pigmented epithelium (RPE) lead to drusen. Thus, it is conceivable to target the retained lipoproteins and seek to remove them. In a case study and pilot multicenter clinical trial, we observed significant regression of drusen and an improvement in visual acuity in patients taking high-dose statin therapy. These results, though preliminary, warrant further investigation.ConclusionFuture treatment of AMD should be based on biology, which will require continued elucidation of the pathogenic mechanisms of AMD development. Neuroprotection represents a potential therapeutic approach, and other promising targets include immune pathways (e.g., inflammation, complement, and inflammasomes) and lipid/lipoprotein accumulation. Finally, due to the heterogeneity of AMD, future progress in therapy will benefit from improved phenotyping and classification.

Roles of HIFs and VEGF in angiogenesis in the retina and brain

“…These results highlight the distinctive roles of HIF-1α and HIF-2α in the context of normal and abnormal retinal vascular development, and they add to a growing body of data that points to the specialization of these 2 transcription factors in other biological contexts (34)(35)(36). The distinctive roles played by the hypoxia response-and, by inference, the production of VEGF-in different retinal cells could be relevant to understanding the response to intraocular administration of anti-VEGF biologics (37).…”

A Perspective of AMD Through the Eyes of Immunology

“…1,2 Unquestionably, the anti-VEGF renaissance has revolutionized treatments for neovascular AMD and prevents (at least in the short term) acute visual loss for millions of individuals. 3 However, we are still treating late in the disease course; therefore, unsurprisingly, atrophy ensues over time. Our focus needs to address and develop new approaches that halt the progressive loss of RPE and photoreceptors that characterize macular degeneration and understanding immune responses in AMD is a tractable target for such therapy.…”

Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization

“…This choroidal neovascularization (CNV) is immature and leaky in nature, resulting in subretinal and intraretinal edema and hemorrhage that can lead to severe vision loss (2,3). Current standard therapy for patients with CNV involves inhibiting vascular endothelial growth factor (VEGF), a molecule that promotes angiogenesis and vascular permeability (3)(4)(5)(6). Despite their therapeutic value, intravitreal injections of anti-VEGF agents act primarily to prevent vascular permeability and resultant edema; thus, constant anti-VEGF injections are necessary to keep these abnormal vessels at bay (4, 5, 7, 8).…”