Oral Delivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses Pathological Choroid Neovascularization

Tarallo, Valeria; Iaccarino, Emanuela; Cicatiello, Valeria; Sanna, Riccardo; Ruvo, Menotti; Falco, Sandro De

doi:10.3390/ijms21020410

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…It shows that levotinib has obvious therapeutic effect on CNV, and the experimental results have reached the expected effect. This is also consistent with the therapeutic effect of levotinib on anti-angiogenesis of tumors shown in the study ( Tarallo et al, 2020 ). The above results lay a credible and direct evidence basis for evaluating the effect of levotinib on CNV.…”

Section: Discussionsupporting

confidence: 92%

Establishing a mouse model of choroidal neovascularization to study the therapeutic effect of levotinib and its mechanism

Xin

Zhu

et al. 2020

Saudi Journal of Biological Sciences

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Objective To study the therapeutic effect and mechanism of levotinib on choroidal neovascularization (CNV) in mice. Methods 45 healthy C57BL/6 mice were selected and randomly divided into three groups: control group (group A), model group (group B) and levotinib group (group C). The model of CNV in mice was established. The fluorescence leakage of choroidal lesions in mice was observed by fundus fluorescein angiography. The morphological changes of retinal vessels in mice were observed by retinal slice preparation, the pathological changes of eyeball tissues in mice were observed by hematoxylin-eosin (HE) staining, the expression of vascular endothelial growth factor (VEGF) in mice retina was detected by real-time quantitative fluorescence PCR, and the protein expression of VEGF in mice retina was detected by Western blotting. Result On the 7th, 14th and 21st day after modeling, compared with group B, the fluorescence leakage area of group C mice was significantly reduced, and the difference was statistically significant (P < 0.05). The morphology of retinal vessels in group A was normal. In group B, the retinal vessels showed large areas of ischemia without perfusion and abundant neovascularization clusters and capillaries. Compared with group B, the morphology of retinal vessels in group C was significantly improved. Group A mice had normal eyeball structure, group B mice had visible spindle-like damage to the inner and outer retina, while group C mice had significantly less spindle-like damage than group B. Compared with group A, group B mice had significantly higher expression of retinal VEGF and the difference was statistically significant (P < 0.05), but compared with group B mice, the expression of VEGF in the retina of mice in group C was significantly decreased, and the difference was statistically significant (P < 0.05). Compared with group A, the expression of VEGF in retina of group B mice was significantly increased, and the difference was statistically significant (P < 0.05). Compared with group B, the expression of VEGF in retina of group C mice was significantly decreased, and the difference was statistically significant (P < 0.05). Conclusion Levatinib has obvious therapeutic effect on CNV, which may be achieved by inhibiting the high expression of VEGF in CNV.

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Section: Discussionsupporting

confidence: 92%

Establishing a mouse model of choroidal neovascularization to study the therapeutic effect of levotinib and its mechanism

Xin

Zhu

et al. 2020

Saudi Journal of Biological Sciences

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“…47 In addition to the possibility of treatment with fewer doses, brolucizumab has excellent fluid control. 48 There is also interest in sustained-release delivery devices for both novel and approved agents, 49–52 in oral anti-VEGF formulations, 53 , 54 and in gene therapy. 55 , 56 The diversity of subject areas covered in wAMD research within an elderly Japanese population was narrow, with some search terms returning little evidence.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Current Treatments for Wet Age-Related Macular Degeneration in Japan: A Systematic Review and Pooled Data Analysis

Takahashi¹,

Iida²,

Ishida³

et al. 2022

OPTH

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Purpose We conducted a systematic review to investigate the effectiveness of clinical treatments for wet age-related macular degeneration (wAMD) in Japanese patients in the decade since anti-vascular endothelial growth factor (VEGF) therapies were introduced. Methods PubMed was searched for articles published in English between 1 January 2008 and 30 September 2018 using a multistring search strategy. Reviews were scanned for additional relevant studies and select gray literature was evaluated. Mean and/or median for the logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), central retinal thickness (CRT), and the number of injections after 12 months of treatment were calculated using extracted data. Data were stratified by disease type and treatment modality. Results Of 335 studies identified, 94 were selected for data extraction (147 treatment arms; typical AMD, n = 25; polypoidal choroidal vasculopathy [PCV], n = 85). Mean (median) logMAR VA was 0.44 (0.32) for typical AMD and 0.34 (0.31) for PCV; the respective mean number of anti-VEGF injections was 5.6 and 4.6. The mean CRT was approximately 220 μm for both groups. For typical AMD, anti-VEGF monotherapy resulted in better VA outcomes than photodynamic therapy (PDT) alone. For PCV, anti-VEGF monotherapy or anti-VEGF plus PDT combination therapy resulted in better VA and CRT outcomes than PDT monotherapy. Combination therapy required fewer injections than anti-VEGF monotherapy (PCV, 3.2 versus 5.3). Conclusion wAMD treatment has advanced dramatically in the years since anti-VEGF drugs were introduced in Japan. Discrete patient populations may benefit from differing management regimens, including the fewer injections required with combination therapy.

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“…The laser CNV model has been used to demonstrate that blocking inflammatory macrophage recruitment strongly reduces CNV ( Akhtar-Schafer et al, 2018 ; Tsutsumi et al, 2003 ). The role of VEGFR1 itself was recently shown in the development of CNV post-laser treatment using a tetrameric tripeptide, iVR1, directed against the receptor and specifically developed as an antagonist of VEGFR1 ( Tarallo et al, 2020 ). Intravitreal administration of iVR1 potently inhibited laser-induced CNV in a dose-dependent manner seven days after laser-included damage (reduction of CNV volume by around 70%, p = 0.0002 compared with DMSO control injections).…”

Section: Role Of Vegfr1 In Age-related Macular Degenerationmentioning

confidence: 99%

VEGFR1 signaling in retinal angiogenesis and microinflammation

Uemura

Fruttiger

D’Amore

et al. 2021

Progress in Retinal and Eye Research

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188

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Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.

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Oral Delivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses Pathological Choroid Neovascularization

Cited by 9 publications

References 37 publications

Establishing a mouse model of choroidal neovascularization to study the therapeutic effect of levotinib and its mechanism

Establishing a mouse model of choroidal neovascularization to study the therapeutic effect of levotinib and its mechanism

Effectiveness of Current Treatments for Wet Age-Related Macular Degeneration in Japan: A Systematic Review and Pooled Data Analysis

VEGFR1 signaling in retinal angiogenesis and microinflammation

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