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Kengo Sumi, Hiroyoshi Hidaka, Yoko Yoshida, Atsuko Kasai, Takashi Izuhara, Masahiko Sugimoto, Mineo Kondo; Therapeutic potential of topical administration of H-1129, an isoquinoline sulfonamide derivative, in wet AMD and proliferative diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):195. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
H-1129 is protein kinase and Hsp-90 inhibitor (ARVO 2012). Eye drop administration of H-1129 produced significant intraocular pressure (IOP) decrease in normal human volunteers at Phase I study. H-1129 will be tested in Phase II study after 2017. In this study, the efficacy of H-1129 eye drop against choroidal neovascularization (CNV) in a rat laser-induced model was investigated at effective doses for IOP reduction therapy.
H-1129 was discovered and synthesized by D. Western Therapeutics Institute, Inc. (DWTI) laboratory. Vascular endothelial growth factor (VEGF) concentration in the culture supernatant of ARPE-19 cells was measured by ELISA following pretreatment with H-1129. Cell migration and proliferation were assessed by wound healing assay with ARPE-19 cells and Cell Counting Kit-8 assay with human retinal microvascularendothelial cells (hRMEC) or human umbilical vascular endothelial cells (HUVEC), respectively. Effects of H-1129 on CNV were investigated in a rat laser-induced CNV model. After laser photocoagulation, Each of H-1129 eye drops (0.5-2%) was topically administered three times per day for two weeks. Progresses of CNV were examined by choroidal flat mount analysis, and evaluated using Image J software. Following topical administration of 2% H-1129 in rats, its concentration in the posterior segment of the eye was measured.
H-1129 decreased VEGF secretion from ARPE-19 cells by 30% (p < 0.05 compared with vehicle) and inhibited migration of them by 51% (p < 0.01 compared with vehicle) at doses of 10 μM and 100 μM, respectively. H-1129 also inhibited proliferations of both hRMEC and HUVEC. A significant reduction of CNV by applying H-1129 was observed dose-dependently and 2%H-1129 reduced CNV by 61% (p < 0.05 compared with vehicle). During two weeks of topical H-1129 administration in rat, cumulative increases of H-1129 and its metabolite, H-1129M1 were confirmed in the retinal pigment epithelium/choroid.
H-1129 has the possibility to be an agent providing a novel therapeutic strategy for proliferative diabetic retinopathy as well as wet AMD, not just as IOP reducing agent. The mechanism of CNV suppression by H-1129 is based on the dual inhibitions of both retinal vascular endothelial cell proliferation and VEGF secretion from ARPE-19 cells.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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