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

2020 ◽  
Vol 21 (2) ◽  
pp. 410 ◽  
Author(s):  
Valeria Tarallo ◽  
Emanuela Iaccarino ◽  
Valeria Cicatiello ◽  
Riccardo Sanna ◽  
Menotti Ruvo ◽  
...  
Keyword(s):  
Intravitreal Injection ◽  
Oral Delivery ◽  
Age Related Macular Degeneration ◽  
Preclinical Model ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Systemic Delivery ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is the primary cause of blindness in advanced countries. Repeated intravitreal delivery of anti-vascular endothelial growth factor (VEGF) agents has represented an important advancement for the therapy of wet AMD with significative results in terms of blindness prevention and partial vision restore. Nonetheless, some patients are not responsive or do not attain significant visual improvement, intravitreal injection may cause serious complications and important side effects have been reported for the prolonged block of VEGF-A. In order to evaluate new anti-angiogenic strategies, we focused our attention on VEGF receptor 1 (VEGFR1) developing a specific VEGFR-1 antagonist, a tetrameric tripeptide named inhibitor of VEGFR 1 (iVR1). We have evaluated its anti-angiogenic activity in the preclinical model of AMD, the laser-induced choroid neovascularization (CNV). iVR1 is able to potently inhibit CNV when delivered by intravitreal injection. Surprisingly, it is able to significantly reduce CNV also when delivered by gavage. Our data show that the specific block of VEGFR1 in vivo represents a valid alternative to the block of VEGF-A and that the inhibition of the pathological neovascularization at ocular level is also possible by systemic delivery of compounds not targeting VEGF-A.

scholarly journals Experimental Models in Neovascular Age Related Macular Degeneration

2020 ◽  
Vol 21 (13) ◽  
pp. 4627
Author(s):  
Olivia Rastoin ◽  
Gilles Pagès ◽  
Maeva Dufies
Keyword(s):  
Macular Degeneration ◽  
Experimental Models ◽  
Age Related Macular Degeneration ◽  
Vascular Endothelial ◽  
In Vivo Models ◽  
Age Related ◽  
Decoy Receptors ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review.

scholarly journals Vascular permeability in retinopathy is regulated by VEGFR2 Y949 signaling to VE-cadherin

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ross O Smith ◽  
Takeshi Ninchoji ◽  
Emma Gordon ◽  
Helder André ◽  
Elisabetta Dejana ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Vascular Permeability ◽  
Geographic Atrophy ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Oxygen Induced Retinopathy ◽  
Age Related ◽  
Endothelial Growth Factor

Edema stemming from leaky blood vessels is common in eye diseases such as age-related macular degeneration and diabetic retinopathy. Whereas therapies targeting vascular endothelial growth factor A (VEGFA) can suppress leakage, side-effects include vascular rarefaction and geographic atrophy. By challenging mouse models representing different steps in VEGFA/VEGF receptor 2 (VEGFR2)-induced vascular permeability, we show that targeting signaling downstream of VEGFR2 pY949 limits vascular permeability in retinopathy induced by high oxygen or by laser-wounding. Although suppressed permeability is accompanied by reduced pathological neoangiogenesis in oxygen-induced retinopathy, similarly sized lesions leak less in mutant mice, separating regulation of permeability from angiogenesis. Strikingly, vascular endothelial (VE)-cadherin phosphorylation at the Y685, but not Y658, residue is reduced when VEGFR2 pY949 signaling is impaired. These findings support a mechanism whereby VE-cadherin Y685 phosphorylation is selectively associated with excessive vascular leakage. Therapeutically, targeting VEGFR2-regulated VE-cadherin phosphorylation could suppress edema while leaving other VEGFR2-dependent functions intact.

scholarly journals Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration

2021 ◽  
Vol 22 (8) ◽  
pp. 3893
Author(s):  
Hye Cheong Koo ◽  
Yi-Yong Baek ◽  
Jun-Sup Choi ◽  
Young-Myeong Kim ◽  
Bokyung Sung ◽  
...  
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Vegf Receptor ◽  
Age Related ◽  
Human Plasminogen ◽  
Endothelial Growth Factor

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.

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