Research ArticleRetinal Disease

The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

Science Translational Medicine  14 Oct 2015:
Vol. 7, Issue 309, pp. 309ra165
DOI: 10.1126/scitranslmed.aac4882

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A new peptide for treating retinal disease

In a new study, Sidman et al. report the inhibitory effect of a peptide drug called Vasotide on blood vessel overgrowth in the retinas of three animal models of human blinding retinal diseases (two rodent and one nonhuman primate). Delivery of Vasotide in eye drops prevented a blood vessel growth-promoting molecule, VEGF, from binding to two different receptors, VEGF receptor-1 and neuropilin-1, expressed by the retinal endothelial cells that line the inner surface of blood vessels.

Abstract

Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and mainly VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. We have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys) [D(CLPRC)], and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors VEGFR-1 and neuropilin-1 (NRP-1). Delivery of Vasotide via either eye drops or intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of ROP decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less-invasive applications to combat pathological angiogenesis in retinal disorders.

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