JP1, a polypeptide specifically targeting integrin αVβ3, ameliorates choroidal neovascularization and diabetic retinopathy in mice

Zhan Xie1, Xin-jing Wu1, Rui-wen Cheng1, Jia-hua Cui2, Song-tao Yuan1, Jian-wei Zhou2, Qing-huai Liu1
1 Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
2 Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
Correspondence to: Song-tao Yuan:, Jian-wei Zhou:, Qing-huai Liu:,
DOI: 10.1038/s41401-022-01005-2
Received: 20 April 2022
Accepted: 21 September 2022
Advance online: 24 October 2022


Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVβ3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 μg) or ranibizumab (RBZ, 10 μg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 μg JP1; a combined IVT injection of JP1 (20 μg) and RBZ (5 μg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 μg) or RBZ (10 μg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVβ3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.
Keywords: choroidal neovascularization; diabetic retinopathy; JP1; oxidative stress; inflammation; angiogenesis

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