The transformation of our basic science understanding of ocular neovascularization to the advent of antivascular endothelial growth factor (VEGF) therapies represents an important milestone in translational medicine. As early as the 1950s, it was postulated that retinal neovascularization was directly related to 'relative retinal anoxia' leading to 'an unknown factor x that develops in the tissue and stimulates new vessel formation'. However, our understanding of retinal disease would depend on progress in oncology research. In the 1970s, it was proposed that tumor growth and progression depends on the ability of a tumor to recruit and support the formation of new blood vessels, which led researchers to pursue a tumor-derived angiogenic factor. In 1989, two Science publications reported groundbreaking advancements in our understanding of angiogenesis. One study reported an endothelial mitogen from pituitary follicular cells, which was named VEGF, whereas another study described a tumor-derived factor purified by its ability to induce vascular permeability, termed vascular permeability factor (VPF). Later research with gene sequencing revealed VEGF and VPF were the same molecules and fundamentally important in angiogenesis. In 1994, researchers identified VEGF as a likely cause of ocular neovascularization.
The first treatment targeting VEGF was bevacizumab (Avastin), a humanized antibody designed to block all VEGF isoforms. In 1997, Genentech (South San Francisco, USA) began trials of bevacizumab for colon cancer, which proved to increase survival time when combined with other chemotherapeutic drugs. In 2004, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of colon cancer. Although anti-VEGF therapies were being developed in oncology, VEGF was found to play a central role in age-related macular degeneration (AMD), leading to the development of pegaptanib (Macugen), an RNA aptamer that neutralizes the VEGF isomer 165. Pegaptanib was shown to decrease vision loss in AMD leading to FDA approval in 2004, making it the first therapeutic agent approved for ocular neovascularization.
Soon after bevacizumab was approved for cancer treatment, systemic intravenous bevacizumab was used in an off-label fashion for the treatment of AMD and was found to significantly improve visual acuity. Ophthalmologists then began using intravitreal bevacizumab injections for AMD, which was found to decrease retinal fluid and improve vision in patients with AMD. As bevacizumab is a relatively large molecule, it was initially expected that the drug would not diffuse through the retina sufficiently to reach the choroid, leading Genentech to develop a truncated, recombinant monoclonal antibody Fab, known as ranibizumab (Lucentis). Ranibizumab was subsequently found to improve visual outcomes for all forms of choroidal neovascularization secondary to AMD in two pivotal trials leading to FDA approval in 2004. In addition to off-label bevacizumab, there are multiple FDA-approved intravitreal anti-VEGF agents including ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron), and brolocizumab (Beovu, Novartis), and intravitreal injection of anti-VEGF agents is the most commonly performed procedure in ophthalmology and possibly all of medicine.
The Wnt signaling pathway is also highly relevant to the field of retina.[13,14] Wnt signaling guides tissue fetal tissue differentiation, contributes to angiogenesis, helps maintain the blood-brain and blood–retinal barrier, and promotes tissue regeneration. There are two Wnt pathways: the canonical/B-Catenin pathway and the noncanonical pathway. Norrin is a strong activator of the canonical Wnt pathway encoded by the Norrie Disease Protein gene on the X-chromosome. Norrin binding to the Frizzled 4-cell surface receptor (FZD4) along with low-density lipoprotein receptor-related protein-5 (LRP5) and tetraspanin family member-12 (TSPAN12) leads to the accumulation of B-catenin, a transcription factor that guides the expression of genes promoting vascular and neural health.
Mutations in components of the Wnt signaling pathway may result in a myriad of neurovascular diseases including Norrie disease, familial exudative vitreoretinopathy, retinopathy of prematurity, and Coats disease. In addition, acquired retinal vascular diseases result in tissue ischemia, vascular leakage, tissue edema, and pathologic neovascularization[18,19] that may be improved with Norrin. Norrin may also promote the repair and maintenance of retinal neural elements.[20–23] As fundamental Wnt actuators (including Norrin, FZD4, LRP5, TSPAN12) remain expressed in the adult retina, activation of the Wnt pathway with exogenous Norrin protein represents a potential therapeutic avenue to treat both inherited and acquired retinal disease.
Curr Opin Ophthalmol. 2020;31(3):207-214. © 2020 Lippincott Williams & Wilkins