Anti-VEGF agents are a rapidly expanding group of therapeutic compounds developed to target pathologic angiogenesis and excessive vascular permeability in cancers and other diseases. They act by blocking the action of the VEGFA ligand or its receptors. Currently, more than 1500 clinical trials of anti-VEGF receptors are underway. The FDA has already approved anti-VEGF agents for the treatment of solid tumors, including colon, breast, and renal cell carcinoma. A number of eye diseases are also characterized by excessive blood vessel growth and permeability, including neovascular age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion (1–6). In a randomized clinical trial, patients with AMD who were treated with intravitreal injections of ranibizumab (Lucentis), which inhibits VEGF ligand binding to its receptor, exhibited improvement in best corrected visual acuity (BCVA) at 12 and 24 months, compared with sham-injected controls (6). These results provided the rationale to consider using these therapies in other retinal diseases characterized by enhanced vascular permeability, such as diabetic retinopathy. In an open-label pilot study in ten patients with diabetic macular edema (DME), multiple intravitreal injections of ranibizumab reduced retinal thickness and improved BCVA at three months (7). Since this original study, seven clinical studies demonstrating positive results for DME have been published (3). While these results are very encouraging and offer potential therapeutic value to many patients, there may be reason for guarded optimism based on a report in this issue of the JCI. Kurihara and colleagues describe dramatic and rapid loss of endothelial cells of the choriocapillaries and severe vision loss secondary to cone cell death in mice following genetic deletion of Vegfa from retinal pigment epithelial (RPE) cells, raising a note of caution regarding long-term use of these drugs (8).

How do these findings relate to the millions of patients treated with anti-VEGF treatments for retinal disease? To date, photoreceptor damage and/or visual loss have not been widely reported in patients receiving these therapies. On the other hand, the situation may be similar to the case of kidney toxicities where only a small proportion of patients develop clinically relevant renal toxicity, while 100% of podocyte-specific knockout mice develop TMA and kidney failure (11). Complete deletion of genes is a “sledge hammer” approach, removing most if not all of the Vegfa produced. These experiments are a practical and important way to reveal functional roles for genes and pathways, but they do not necessarily recapitulate clinical circumstances. Not only is the degree of knockdown much lower with drug inhibition, but the treatment is intermittent, including drug-free periods that may allow recovery of damaged endothelium. Furthermore, it is likely that susceptibility is determined by other modifying genetic factors; identification of these will be important going forward.

Given the ongoing role of VEGFA for maintenance of the retinal vasculature, are there alternative strategies to treating vascular diseases of the eye? In their paper, Kurihara and colleagues also deleted hypoxia inducible factor 1 α (Hif1a) and hypoxia inducible factor 2 α (Epas1) from RPE cells (8). HIFs are basic-helix-loop helix transcription factors that regulate VEGFA production, and similar to VEGFA, their expression is upregulated in retinal diseases. In contrast to VEGF deletion, loss of Hif1a and/or Epas1 did not cause vision loss or endothelial damage in mice. However, elimination of these factors rescued pathologic angiogenesis in the laser photocoagulation model of choroidal neovascularization. The authors suggest that Hifs may be a more desirable target in eye disease, shutting down pathologic angiogenesis without damaging healthy vessels, perhaps by more modest regulation of endogenous VEGFA levels. Nonetheless, feasibility of this approach in patients and/or experimental models must be established. Although VEGFA is one of the best-known targets of the HIF pathway, endogenous levels of Vegfa were preserved in the RPE-Hif–knockout mice. This suggests a dominant role for Hif-independent regulation of Vegfa or perhaps that actual deletion of the Hif allele(s) was lower than the 68% efficiency rate suggested by experiments in reporter mice (8). Combination angiostatic therapies, which include induction with an anti-VEGF agent and maintenance with a non-VEGF agent with angiostatic properties, is another possibility (17).