Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 21, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1921252118
Keywords
angiogenesis; VEGF; age-related macular degeneration
Categories
Funding
- NIH [EY031345]
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Neovascularization is a key feature of severe vision loss diseases like ischemic retinal diseases and wet AMD, and VEGF inhibitors have transformed the treatment of these disorders. However, many patients in real-life clinical settings do not experience the same benefits as in clinical trials, emphasizing the urgent need for novel long-acting VEGF inhibitors.
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.
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