Efficacy of a marine natural product on experimental ocular angiogenesis

Abstract

Purpose : A subset of patients with retinal angiogenic disease such as diabetic retinopathy do not respond or respond poorly to anti-VEGF agents, and targeting alternative mechanisms of angiogenesis, possibly in combination with anti-VEGF agents, is a major goal in ocular angiogenesis research. We investigated the impact of a marine natural product, SIPRAD0279, which was modified for reduced toxicity, on experimental ocular angiogenesis.

Methods : The effect of SIPRAD0279 on angiogenesis was studied using ex vivo and in vivo angiogenesis assays, including choroid and metatarsal sprouting assays, aortic ring assay and in the mouse model of oxygen induced retinopathy (OIR). After the treatment with SIPRAD0279, organ explants and retina flatmounts were subjected to immunofluorescence staining with vascular markers for quantitative analysis of blood vessel formation.

Results : SIPRAD0279 completely blocked vessel outgrowth from choroid, metatarsal and aortic explants at 300pM with IC50=130.5±22 pM. Interestingly, SIPRAD0279 had no impact on preformed choroidal vasculature at this dosage. In the mouse model of OIR, intraperitoneal injection of 0.25 mg/kg SIPRAD0279 caused significant inhibition on pathological neovascularization without affecting physiological blood vessel re-growth in the retina.

Conclusions : Our study demonstrates that a modified marine natural product (SIPRAD0279) is a potent angiogenic inhibitor that selectively inhibits pathological neovascularization in the retina and not choroid. SIPRAD0279 could be further developed as an alternative treatment strategy for ocular diseases such as proliferative diabetic retinopathy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.