Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.

Autor:	Canonica J; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Foxton R; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Garrido MG; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Lin CM; Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United States., Uhles S; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Shanmugam S; Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United States., Antonetti DA; Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United States., Abcouwer SF; Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United States., Westenskow PD; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular neuroscience [Front Cell Neurosci] 2023 Jun 12; Vol. 17, pp. 1192464. Date of Electronic Publication: 2023 Jun 12 (Print Publication: 2023).
DOI:	10.3389/fncel.2023.1192464
Abstrakt:	Introduction: Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation. Methods: We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries. Results: In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration. Discussion: These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials. Competing Interests: JC, RF, SU, and PW are employees of F. Hoffmann-La Roche Ltd., Roche Pharma AG, or Genentech, Inc. MG was an employee of F. Hoffmann-La Roche Ltd. at the time the studies described in this manuscript were performed and is a current employee of Boehringer Ingelheim (Schweiz) GmbH. DA and SA have received research funding from F. Hoffmann-La Roche Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from F. Hoffmann-La Roche Ltd. The funder had the following involvement with the study: study design; conducting the study; data collection, management, analysis, interpretation, preparation, review, and approval of the manuscript. Funding was provided by F. Hoffmann-La Roche Ltd. for third-party writing assistance, which was provided by Luke Carey, Ph.D., CMPP, of Envision Pharma Group. (Copyright © 2023 Canonica, Foxton, Garrido, Lin, Uhles, Shanmugam, Antonetti, Abcouwer and Westenskow.)
Databáze:	MEDLINE
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