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Sergio Caballero, Jacob Beverage, Ippei Usui, Maria Grant; A Cortistatin Derivative Proves Efficacious Against Experimental Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4955.
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© ARVO (1962-2015); The Authors (2016-present)
Cortistatins are a class of steroidal alkaloids originally isolated from a marine sponge, Corticulum simplex, and shown to have potent antiangiogenic properties. We hypothesized that a proprietary derivative of cortistatin A (SMD-02-1001) would be effective at reducing experimentally induced choroidal neovascularization (CNV).
SMD-02-1001 was first assessed in vitro using cultured human umbilical vein endothelial cells (HUVECs) in a proliferation assay. Antiangiogenic potential was examined in vivo using two models of murine ocular neovascularization. The neonatal oxygen-induced retinopathy (OIR) model was used to test the effect of a single injection of SMD-02-1001 at doses ranging from 0.001 to 10 uM on retinal neovascularization. The adult model of Bruch’s membrane rupture by laser application was used to test the effect of 0.001 to 10 uM SMD-02-1001 on CNV.
SMD-02-1001 inhibited HUVEC proliferation with an IC50 of 5 nM. SMD-02-1001 did not appear to inhibit retinal neovascularization in the OIR animals. However, the compound showed a concentration-dependent trend toward decreasing the amount of vaso-obliteration observed. SMD-02-1001 was highly effective at reducing CNV lesion volume in a concentration-dependent manner, resulting in a 2.5-fold decrease in lesion volume at a dose of 10 nM, and tapering to a 3-fold reduction at 10 uM.
The need for additional antiangiogenic agents to be used either in combination with existing therapies or by themselves in the treatment of exudative age-related macular degeneration continues. A significant patient population exists that is refractive to therapeutic agents in current use. We demonstrated that a cortistatin derivative, SMD-02-1001, may be a candidate for such an additional agent. While SMD-02-1001 had no demonstrated effect on reducing retinal neovascularization in a model of OIR, the data suggest it may mitigate vaso-obliteration. More importantly, SMD-02-1001 significantly reduced CNV lesion volume in a Bruch’s membrane injury model. Further exploration of SMD-02-1001’s potential as a therapeutic agent in age-related macular degeneration is certainly warranted.
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