Tyrosine kinase blocking collagen IV–derived peptide suppresses ocular neovascularization and vascular leakage

Silva, Raquel Lima e; Kanan, Yogita; Mirando, Adam C.; Kim, Jayoung; Shmueli, Ron B.; Lorenc, Valeria E.; Fortmann, Seth D.; Sciamanna, Jason; Pandey, Niranjan B.; Green, Jordan J.; Popel, Aleksander S.; Campochiaro, Peter A.

doi:10.1126/scitranslmed.aai8030

Cited by 45 publications

(38 citation statements)

References 55 publications

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“…This is particularly important as, in addition to its role in promoting vascular leakage by inhibiting Tie2 phosphorylation, Ang2 also promotes inflammation by enhancing the effects of TNFα. We have previously shown that Ang2 overexpression alone was sufficient to increase leakage in retinal vessels [ 28 ] and, here, we demonstrate that Ang2 can enhance TNFα-mediated permeability relative to TNFα alone ( Figure 5 B). These data are consistent with the observations that the release of Ang2 stored within ECs by TNFα sensitizes ECs to TNFα stimulation [ 24 ].…”

Section: Discussionsupporting

confidence: 74%

“…AXT107 is a non-RGD 20-mer α v β 3 and α 5 β 1 integrin-binding peptide that has previously been shown to inhibit VEGF signaling and stimulate Tie2 through the conversion of the normally inhibitory Ang2 into an activator [ 28 , 29 ]. When injected into the eye, the effects of AXT107 are sustained over a period of at least two months through the formation of a slow-release gel in the vitreous [ 28 ]. Furthermore, intraocular injection of AXT107 strongly suppresses VEGF-induced vascular leakage, but also reduces vascular leakage induced by intraocular injection of lipopolysaccharide (LPS) [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

Mirando

Silva

Chu

et al. 2020

IJMS

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Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

Mirando

Silva

Chu

et al. 2020

IJMS

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“…Therefore, achieving a sustained suppression of neovascularization would necessitate some form of sustained delivery, such as a microparticle-based delivery system that encapsulates nanoparticles formulated with a therapeutic peptide; 12 in addition, a therapeutic peptide has been shown to form a natural depot upon injection and that is slowly released from the depot. 12 , 13 …”

Section: Discussionmentioning

confidence: 99%

“… 12 Recently, a collagen IV–derived peptide has been demonstrated in several animal models to significantly reduce neovascularization and vascular leakage. 13 To reduce the frequency of injections and to prolong the action of the antiangiogenic peptides, peptide-containing microparticles that slowly release peptide over an extended period of time can be injected to provide sustained inhibition of neovascularization and vascular leakage. Effective antiangiogenic agents including small molecule tyrosine kinase inhibitors, peptides, antibodies, siRNAs, or genes can be intraocularly delivered as treatment.…”

mentioning

confidence: 99%

Three-Dimensional Transport Model for Intravitreal and Suprachoroidal Drug Injection

Zhang

Bazzazi

Silva

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeQuantitative understanding of the transport of therapeutic macromolecules following intraocular injections is critical for the design of efficient strategies in treating eye diseases, such as neovascular (wet) age-related macular degeneration (AMD) and macular edema (ME). Antiangiogenic treatments, such as neutralizing antibodies against VEGF or recently characterized antiangiogenic peptides, have shown promise in slowing disease progression.MethodsWe developed a comprehensive three-dimensional (3D) transport model for intraocular injections using published data on drug distribution in rabbit eyes following intravitreal and suprachoroidal (SC) injection of sodium fluorescein (SF), bevacizumab, and ranibizumab. The model then was applied to evaluate the distribution of small molecules and antiangiogenic proteins following intravitreal and SC injections in human eyes.ResultsThe model predicts that intravitreally administered molecules are substantially mixed within the vitreous following injection, and that the long-term behavior of the injected drug does not depend on the initial mixing. Ocular pharmacokinetics of different drugs is sensitive to different clearance mechanisms. Effective retinal drug delivery is impacted by RPE permeability. For VEGF antibody, intravitreal injection provides sustained delivery to the retina, whereas SC injection provides more efficient, but short-lived, retinal delivery for smaller-sized molecules. Long-term suppression of neovascularization through SC administration of antiangiogenic drugs necessitates frequent injection or sustained delivery, such as microparticle-based delivery of antiangiogenic peptides.ConclusionsA comprehensive 3D model for intravitreal and SC drug injection is developed to provide a framework and platform for testing drug delivery routes and sustained delivery devices for new and existing drugs.

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“…However, chemical lesion, anoxia, or inflammation disrupts the balance between angiogenic and anti-angiogenic factors. Capillaries invade from the limbal vascular plexus, leading to the occurrence of corneal neovascularization [2-4]. Neovascular capillaries are often accompanied by bleed or contract, eventually leading to blindness [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Osthole: A Traditional Chinese Medicine for Ocular Anti-Angiogenic Therapy

et al. 2020

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Osthole is an agent isolated from Cnidium monnieri (L.) Cusson and has been used to treat several disorders. Corneal neovascularization is a sight-threatening condition associated with several inflammatory or infectious ocular disorders. In this study, we investigated the anti-angiogenic effects of osthole on corneal neovascularization and the underlying mechanism. Methods: MTT assay, HE staining, and calcein-AM/propidium iodide staining was conducted to detect the toxicity of osthole in vitro and in vivo. Corneal neovascularization of ICR mice was induced by alkali burn and observed by a slit lamp microscopy on day 7 after alkali injury. EdU assay, Ki67 immunofluorescence assay, Transwell migration assay, and Matrigel assay were conducted to investigate the role of osthole in endothelial angiogenic effects in vitro. Western blots were conducted to investigate the anti-angiogenic mechanism of osthole in corneal neovascularization. Results: Administration of osthole ranging from 0.05 to 25 µM had no detectable cytotoxicity or tissue toxicity in vivo and in vitro. Topical administration of osthole inhibited corneal neovascularization induced by alkali burn. Osthole decreased the proliferation, migration, and tubeformation of endothelial cells induced by VEGF. Osthole inhibited endothelial angiogenic functions through blocking the phosphorylation of ERK1/2, JNK, and p38. Conclusion: Our study provides evidence that osthole is a promising drug for the treatment of corneal neovascularization.

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Tyrosine kinase blocking collagen IV–derived peptide suppresses ocular neovascularization and vascular leakage

Cited by 45 publications

References 55 publications

Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

Three-Dimensional Transport Model for Intravitreal and Suprachoroidal Drug Injection

Osthole: A Traditional Chinese Medicine for Ocular Anti-Angiogenic Therapy

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