Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases
Title:
Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases
Other Titles:
Investigative Ophthalmology & Visual Science
Keywords:
Publication Date:
01 July 2019
Citation:
Beiying Qiu, Alison Tan, Amutha Barathi Veluchamy, Yong Li, Hannah Murray, Wei Cheng, Chenghao Liu, Joanna Marie Busoy, Qi-Yin Chen, Srivani Sistla, Walter Hunziker, Chui Ming Gemmy Cheung, Tien Yin Wong, Wanjin Hong, Hendrik Luesch, Xiaomeng Wang; Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases. Invest. Ophthalmol. Vis. Sci. 2019;60(8):3254-3263. doi: https://doi.org/10.1167/iovs.19-26936.
Abstract:
Purpose: Abnormal blood vessel formation is a defining feature of many blinding eye diseases. Targeting abnormal angiogenesis by inhibiting VEGF has revolutionized the treatment of many ocular angiogenic diseases over the last decade. However, a substantial number of patients are refractory to anti-VEGF treatment or may develop resistance over time. The objective of this study was to determine the efficacy and the mechanism of action of Apratoxin S4 in ocular angiogenesis. Methods: Retinal vascular cell proliferation, migration, and the ability to form tube-like structure were studied in vitro. Ex vivo aortic ring, choroid, and metatarsal assays were used to study Apratoxin S4's impact on vessel outgrowth in a multicellular environment. Apratoxin S4 was also tested in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), and in a rabbit model of persistent retinal neovascularization (PRNV). Western blot and ELISA were used to determine the expression of key angiogenic regulators after Apratoxin S4 treatment. Results: Apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing multiple angiogenic pathways. VEGF-activated vascular cells and angiogenic vessels are more susceptible to Apratoxin S4 treatment than quiescent vascular cells and vessels. Both intraperitoneal and intravitreal delivery of Apratoxin S4 are able to impede ocular neovascularization in vivo. Apratoxin S4 specifically attenuates pathological ocular angiogenesis and exhibits a combinatorial inhibitory effect with standard-of-care VEGF inhibitor drug (aflibercept). Conclusions: Apratoxin S4 is a potent antiangiogenic drug that inhibits the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
Supported by grants from the Singapore Biomedical Research Council-Strategic Positioning Fund (SIPRAD; Singapore) to TYW and WJH, National Medical Research Council Singapore Cooperative Basic Research Grant (NMRC/CBRG/0058/2014; Singapore) to XW and WJH, and the Start Up Grant from the Lee Kong Chian School of Medicine, Nanyang Technological University (Singapore) to XW. Apratoxin S4 was provided by Oceanyx Pharmaceuticals (Woburn, MA, USA) and its synthesis was supported in part by Bankhead-Coley Cancer Research Program, Technology Transfer Feasibility grant 3BF03 to HL (Tallahassee, FL, USA).
Description:
ISSN:
0146-0404
1552-5783
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