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

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

Research output: Contribution to journalArticle

Abstract

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 predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c-Met, and PDGFRβ. Optimal signaling through these receptors requires complex formation with b3 integrin, which was reduced by AXT107 binding to αvβ3. AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins.

Original languageEnglish (US)
Article numbereaai8030
JournalScience Translational Medicine
Volume9
Issue number373
DOIs
StatePublished - Jan 18 2017

ASJC Scopus subject areas

  • Medicine(all)

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