Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion
IntroductionClinical 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 dege...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1192464/full |
| _version_ | 1797806336190185472 |
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| author | Jérémie Canonica Richard Foxton Marina Garcia Garrido Cheng-Mao Lin Sabine Uhles Sumathi Shanmugam David A. Antonetti Steven F. Abcouwer Peter D. Westenskow |
| author_facet | Jérémie Canonica Richard Foxton Marina Garcia Garrido Cheng-Mao Lin Sabine Uhles Sumathi Shanmugam David A. Antonetti Steven F. Abcouwer Peter D. Westenskow |
| author_sort | Jérémie Canonica |
| collection | DOAJ |
| description | IntroductionClinical 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.MethodsWe 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.ResultsIn 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.DiscussionThese 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. |
| first_indexed | 2024-03-13T06:05:48Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-03-13T06:05:48Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-eb987d4d51b2489f96e27b6a29635f5b2023-06-12T04:34:14ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-06-011710.3389/fncel.2023.11924641192464Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusionJérémie Canonica0Richard Foxton1Marina Garcia Garrido2Cheng-Mao Lin3Sabine Uhles4Sumathi Shanmugam5David A. Antonetti6Steven F. Abcouwer7Peter D. Westenskow8Roche Pharma Research and Early Development, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center, Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center, Basel, SwitzerlandDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United StatesRoche Pharma Research and Early Development, Roche Innovation Center, Basel, SwitzerlandDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United StatesDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, Ann Arbor, MI, United StatesRoche Pharma Research and Early Development, Roche Innovation Center, Basel, SwitzerlandIntroductionClinical 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.MethodsWe 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.ResultsIn 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.DiscussionThese 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.https://www.frontiersin.org/articles/10.3389/fncel.2023.1192464/fullangiopoietin-2choroidal neovascularizationdiabetic macular edemaneovascular age-related macular degenerationvascular endothelial growth factor-A |
| spellingShingle | Jérémie Canonica Richard Foxton Marina Garcia Garrido Cheng-Mao Lin Sabine Uhles Sumathi Shanmugam David A. Antonetti Steven F. Abcouwer Peter D. Westenskow Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion Frontiers in Cellular Neuroscience angiopoietin-2 choroidal neovascularization diabetic macular edema neovascular age-related macular degeneration vascular endothelial growth factor-A |
| title | Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion |
| title_full | Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion |
| title_fullStr | Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion |
| title_full_unstemmed | Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion |
| title_short | Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion |
| title_sort | delineating effects of angiopoietin 2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia reperfusion |
| topic | angiopoietin-2 choroidal neovascularization diabetic macular edema neovascular age-related macular degeneration vascular endothelial growth factor-A |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1192464/full |
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