Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep25509
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Funding
- International Retinal Research Foundation
- Retina Research Foundation
- Bright Focus Foundation
- NIH/NEI [R01EY025641, R01EY018358]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2013R1A1A2007151]
- NIH/NCATS [KL2TR001106]
- Research to Prevent Blindness, Inc.
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Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 mu M) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 mu M SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.
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