期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：21
DOI：10.1073/pnas.1921252118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of intraocular vascular disorders. However, the burden of frequent intravitreal injections reduces patient compliance such that the impact in the “real world” is less than in clinical trials. Thus, there is a need to discover VEGF inhibitors than can be administered less frequently. We hypothesized that the ability to bind heparan-sulfate proteoglycans may be a strategy to promote intraocular retention and increase half-life. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics that are more effective and durable in action in animal models of intraocular neovascularization than a standard of care like aflibercept. The work should fulfill an unmet medical need and advance therapy.
Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.
