Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders

Abstract

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.

LIF, a mitogen for choroidal endothelial cells, protects the choriocapillaris: implications for prevention of geographic atrophy

“…Pyrogen‐free reagents were employed. To inactivate endotoxin, columns and equipment (Akta Explorer System, GE Healthcare) were sanitized prior to use by exposure to 0.5 N NaOH for approximately 40 min, as described (Xin et al , 2021). LPS levels were measured by ToxinSensor™ Chromogenic LAL Endotoxin Assay Kit (GenScript, Cat.…”

Vascular tortuosity quantification as an outcome metric of the oxygen-induced retinopathy model of ischemic retinopathy

“…The next series of experiments were performed to investigate the effects of known therapeutic agents on vascular tortuosity in OIR mice using another previously published dataset. (11) Previous reports have demonstrated that intravitreal injections of aflibercept decrease neovascularization and retinal inflammation in OIR mice, but the effects of aflibercept on vascular tortuosity remain unknown.…”

“…The second dataset was previously published by Xin et al and consisted of pooled flat-mount retinal images from OIR mice intravitreally injected with aflibercept versus IgG contralaterally as control. (11)…”

Modern Wound Dressings: Hydrogel Dressings

“…Biodegradation of hydrogels with chemical polymerization is dependent not only on the nature of the biopolymer but also on stability of crosslinking bonds. For instance, the biodegradable hydrogels were obtained by use of MMP-specific peptide linkers and it was shown that degradation of these hydrogels is matched with cell growth and spreading in culture [ 43 ]. Flexible degradation kinetics mediates an application of hydrogels as delivery vehicles for drugs or as biological active substances.…”