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J. W. Maxwell, A. C. Hughes, S. Wolkenberg, Z. Zhao, T. P. McDonald, C. J. Thut, A. L. Webber; Sstr2 Agonist Effects on Ocular Neovascular Disease. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2646. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular neovascular disease is the final common pathway of a number of ocular diseases such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR) and exudative age-related macular degeneration (AMD). The growth hormone (GH) axis plays an important role in neovascularization. In preclinical and clinical studies, decreased levels of GH inhibit IGF-1 production and levels of IGF-1 are correlated with the degree of neovascularization in PDR. Since somatostatin regulates the production of GH, somatostatin and its receptors are of interest as therapeutic targets. Somatostatin receptor 2 (SSTR2) is involved in GH secretion and therefore may be important in treating ocular neovascular disease. We tested two Merck SSTR2 agonists in in vivo models of neovascularization.
SSTR2 agonists A and B were first evaluated in a rat model for evaluating GH levels. GH was artificially increased using a GH secretagogue, and compound effects on the GH spike were evaluated with a radioactive assay. Next, efficacy was evaluated in a rat ROP model. Newborn rats were exposed to cycling oxygen for 2 weeks followed by one week of systemic dosing with SSTR2 agonist A. Retinal neovascularization was evaluated by measuring the total area of neovascular tufts in retinal flatmounts. Finally, SSTR2 agonist B was evaluated in a rat choroidal neovascularization (CNV) model. Animals received a local intravitreal injection of the compound every 4 days during the study. Area of neovascularization was evaluated in these animals by perfusing with a FITC-dextran solution. Total lesion area was then quantified using fluorescent microscopy.
SSTR2 agonists A and B showed a statistically significant decrease in GH levels in the GH assay. The compounds were able to decrease the GH spike by ~85% when compared to vehicle controls. In the ROP model, SSTR2 agonist A did not affect the area of neovascularization in the retina. When dosed locally in the CNV model, SSTR2 agonist B did significantly decrease lesion area in these animals ~50% when compared to the vehicle control.
Systemic administration of Merck SSTR2 agonist compounds has shown efficacy in the GH axis by affecting GH levels in rats. Work done by others has suggested that systemic dosing of SSTR2 agonists decreases neovascularization in oxygen induced retinopathy models. Despite compound levels expected to decrease GH, systemic delivery of the Merck SSTR2 agonist failed to decrease neovascularization in the ROP model. When dosed locally, however, an SSTR2 compound decreases neovascularization in the rat laser CNV model.
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