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

Published on May 25, 2021in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.1921252118
Hong Xin2
Estimated H-index: 2
(UCSD: University of California, San Diego),
Nilima Biswas16
Estimated H-index: 16
(UCSD: University of California, San Diego)
+ 4 AuthorsNapoleone Ferrara179
Estimated H-index: 179
(UCSD: University of California, San Diego)
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.
#1Yusuke Ichiyama (Shiga University of Medical Science)H-Index: 8
#2Shumpei Obata (Shiga University of Medical Science)H-Index: 2
Last. Masahito Ohji (Shiga University of Medical Science)H-Index: 33
view all 8 authors...
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness and intravitreal anti-vascular endothelial growth factor (VEGF) injection is becoming a first-line choice for treatment of ROP. However, there is a major concern that intravitreally injected anti-VEGF agents could escape from the eye into the systemic circulation and impair systemic development. Moreover, escaped anti-VEGF agents could have an effect on the retina of the fellow eye. In this study, we investigated the hema...
#1Zhong Cuiling (UCSD: University of California, San Diego)H-Index: 2
#2Pin Li (UCSD: University of California, San Diego)H-Index: 1
Last. Napoleone Ferrara (UCSD: University of California, San Diego)H-Index: 179
view all 10 authors...
Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. Here we report the identification of the hexosamine D-mannosamine (ManN) as an EC mitogen and survival factor for bovine and human microvascular EC, with an additivity with VEGF. ManN inhibits glycosylation in ECs and induces significant changes in N-glycan and O-glycan profiles. We further demonstrate that ManN and two N-glycosylation inhibitors stimulate EC proliferation via both JNK activation and th...
#1Caroline R. Baumal (Tufts University)H-Index: 38
#2Richard F. SpaideH-Index: 107
Last. Thomas A. Albini (UM: University of Miami)H-Index: 33
view all 18 authors...
Purpose To evaluate the features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6mg/0.05ml for treatment of neovascular age-related macular degeneration (AMD). Design Retrospective case series. Participants Fifteen eyes from 12 patients identified from 10 centers in the United States. Methods Review of patient demographics, ophthalmologic examination and retinal imaging. Main Outcome Measures Baseline and follow-...
43 CitationsSource
#1Peter A. Campochiaro (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 121
#2Dennis M. MarcusH-Index: 34
Last. Giulio Barteselli (Genentech)H-Index: 20
view all 15 authors...
Purpose To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. Design Phase 2, multicenter, randomized, active treatment–controlled clinical trial. Participants Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti–vascular endothelial growth factor intravitreal injections and were responsive to treatment. Methods Patients were randomized 3:3:3:2 to receive the PDS fill...
73 CitationsSource
#1Rajendra S. Apte (WashU: Washington University in St. Louis)H-Index: 37
#2Daniel S. ChenH-Index: 40
Last. Napoleone Ferrara (UCSD: University of California, San Diego)H-Index: 179
view all 3 authors...
The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regu...
274 CitationsSource
Purpose: DARPin molecules are a novel class of small proteins that contain engineered ankyrin repeat domain(s) and bind to target proteins with high specificity and affinity. Abicipar-pegol (abicipar), a DARPin molecule targeting vascular endothelial growth factor-A (VEGF-A), is currently under evaluation in patients with age-related macular degeneration. The pharmacodynamic properties of abicipar were characterized using in vivo and in vitro assays. Methods: The binding affinity of abicipar was...
26 CitationsSource
#1Sa Xiao (UW: University of Washington)H-Index: 4
#2Felicitas Bucher (Scripps Research Institute)H-Index: 12
Last. Aaron Y. LeeH-Index: 26
view all 11 authors...
: Oxygen-induced retinopathy (OIR) is a widely used model to study ischemia-driven neovascularization (NV) in the retina and to serve in proof-of-concept studies in evaluating antiangiogenic drugs for ocular, as well as nonocular, diseases. The primary parameters that are analyzed in this mouse model include the percentage of retina with vaso-obliteration (VO) and NV areas. However, quantification of these two key variables comes with a great challenge due to the requirement of human experts to ...
14 CitationsSource
#1Sandra Markovic-Mueller (Paul Scherrer Institute)H-Index: 3
#2Edward Stuttfeld (University of Basel)H-Index: 8
Last. Kurt Ballmer-Hofer (Paul Scherrer Institute)H-Index: 44
view all 9 authors...
Summary Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex...
39 CitationsSource
#1Raquel Lima e Silva (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 17
#2Yogita Kanan (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 4
Last. Peter A. Campochiaro (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 121
view all 12 authors...
Vascular endothelial growth factor (VEGF)–neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model ...
21 CitationsSource
#1Jörg T. Regula (Hoffmann-La Roche)H-Index: 11
Last. Guido Hartmann (Hoffmann-La Roche)H-Index: 13
view all 18 authors...
Abstract Anti‐angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor‐A (VEGF‐A) have revolutionized treatment of retinal vascular diseases including age‐related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti‐VEGF‐A monotherapy efficacy by targeting both VEGF‐A and angiopoietin‐2 (ANG‐2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of it...
76 CitationsSource
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