Corneal neovascularization is inhibited with nucleolin-binding aptamer, AS1411

Vivanco-Rojas, Óscar; García‐Bermúdez, Mariana Yolotzin; Iturriaga-Goyón, Emilio; Rebollo, Wolfgang; Buentello-Volante, Beatríz; Magaña‐Guerrero, Fátima Sofía; Bates, Paula J.; Pérez‐Torres, Armando; Garfias, Yonathan

doi:10.1016/j.exer.2020.107977

Cited by 16 publications

(18 citation statements)

References 46 publications

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“…However, the gene expression levels are not relevant to function of nucleolin in angiogenesis, because its function is related to its translocation to cell surface. It was recently shown that nucleolin is translocated to the EC surface in neovascular blood vessels in OIR, whereas it stayed nuclear in the normoxic conditions (Garfias et al, 2019). Similar nucleolin translocation takes place in corneal neovascularization and nucleolin-binding DNA aptamer was able to inhibit corneal neovascularization (Vivanco-Rojas et al, 2020).…”

Section: Proteins Involved In Mechanotransduction Are Upregulated In mentioning

confidence: 98%

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

2020

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Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and the most widely used model for ischemic retinopathies, such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and retinal vein occlusion (RVO). OIR model has been used to test new potential anti-angiogenic factors for human diseases. We have recently performed the most comprehensive characterization of OIR by a relatively novel mass spectrometry (MS) technique, sequential window acquisition of all theoretical fragment ion mass spectra (SWATH-MS) proteomics and used genetically modified mice strains to identify novel molecular drug targets in angiogenic retinal diseases. We have confirmed the relevance of the identified molecular targets to human diseases by determining their expression pattern in neovascular membranes obtained from PDR and RVO patients. Based on our results, crystallins were the most prominent proteins induced by early hypoxic environment during the OIR, while actomyosin complex and Filamin A-R-Ras axis, that regulates vascular permeability of the angiogenic blood vessels, stood out at the peak of angiogenesis. Our results have revealed potential new therapeutic targets to address hypoxia-induced pathological angiogenesis and the associated vascular permeability in number of retinal diseases.

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Section: Proteins Involved In Mechanotransduction Are Upregulated In mentioning

confidence: 98%

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

2020

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“…On the other hand, there are pluripotent stem cells which act as a self‐reparative stimuli for damaged eye tissues like human retinal progenitor cells for retinopathies treatment 149 and bone marrow‐derived stem cells for AMD treatment 150 that are being studied. Finally, there are also aptamers that are single‐stranded oligonucleotides capable of specifically binding the target with high affinity recognition such as those that acting by inhibition of bFGF 151 and nucleolin, an inside nucleus protein associated with corneal neovascularization 152 . In comparison with the other groups of molecular modalities, the gene‐based therapies are new in the therapeutics field, so all efforts are toward new molecules development.…”

Section: Developing Molecules and Therapies For Treatment Of Ocular Amentioning

confidence: 99%

“…Finally, there are also aptamers that are single-stranded oligonucleotides capable of specifically binding the target with high affinity recognition such as those that acting by inhibition of bFGF 151 and nucleolin, an inside nucleus protein associated with corneal neovascularization. 152 In comparison with the other groups of molecular modalities, the gene-based therapies are new in the therapeutics field, so all efforts are toward new molecules development. The main molecules in development and therapies for the treatment of ocular angiogenesis are summarized in Table 3.…”

Section: Cw-703mentioning

confidence: 99%

Biological drug therapy for ocular angiogenesis: Anti‐VEGF agents and novel strategies based on nanotechnology

Formica

Alfonso

Palma

2021

Pharmacology Res & Perspec

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Currently, biological drug therapy for ocular angiogenesis treatment is based on the administration of anti‐VEGF agents via intravitreal route. The molecules approved with this purpose for ocular use include pegaptanib, ranibizumab, and aflibercept, whereas bevacizumab is commonly off‐label used in the clinical practice. The schedule dosage involves repeated intravitreal injections of anti‐VEGF agents to achieve and maintain effective concentrations in retina and choroids, which are administrated as solutions form. In this review article, we describe the features of different anti‐VEGF agents, major challenges for their ocular delivery and the nanoparticles in development as delivery system of them. In this way, several polymeric and lipid nanoparticles are explored to load anti‐VEGF agents with the aim of achieving sustained drug release and thus, minimize the number of intravitreal injections required. The main challenges were focused in the loading the molecules that maintain their bioactivity after their release from nanoparticulate system, followed the evaluation of them through studies of formulation stability, pharmacokinetic, and efficacy in in vitro and in vivo models. The analysis was based on the information published in peer‐reviewed published papers relevant to anti‐VEGF treatments and nanoparticles developed as ocular anti‐VEGF delivery system.

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“…The aim of this study arose from the fact that NCL is a nucleolar protein involved in cell growth, survival and tumorigenesis. Previous studies in our group revealed that there is a cell surface localization of NCL in angiogenic cells in a suture-induced corneal neovascularization model [ 44 ] and that AS411 was able to inhibit corneal neovascularization downregulating the angiogenic miR-21 and-221 molecules [ 45 ]. Our results are consistent with previous studies where intravitreal injection or topical application of G-Quartet aptamer targeting NCL ameliorated choroidal neovascularization in a model of age-related macular degeneration [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this context, our laboratory documented for the first time that NCL is able to translocate onto the de-novo endothelial cell surface after an angiogenic stimulus in an in vivo corneal neovascularization model, and this translocation was abolished when bevacizumab was topically applied, suggesting a direct effect of VEGF in NCL cell surface translocation in aberrant corneal neovessels [ 44 ]. Moreover, we have recently described that topical application of nucleolin-binding aptamers AS1411, formerly known as AGRO100, inhibit VEGF-mediated corneal angiogenesis downregulating miR-21 and -221 proangiogenic miRNAs [ 45 ]. Aptamers are short single-stranded oligonucleotides that have biological properties that overcome monoclonal antibodies.…”

Section: Introductionmentioning

confidence: 99%

AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation

Iturriaga-Goyón

Vivanco-Rojas

Magaña‐Guerrero

et al. 2021

IJMS

Self Cite

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Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.

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Corneal neovascularization is inhibited with nucleolin-binding aptamer, AS1411

Cited by 16 publications

References 46 publications

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

Biological drug therapy for ocular angiogenesis: Anti‐VEGF agents and novel strategies based on nanotechnology

AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation

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