Purchase this article with an account.
Jack Henkin, Ignacio Melgar-Asensio, Soesiawati R. Darjatmoko, Shoujian Wang, Christine M. Sorenson, Daniel M Albert, Reshma Bhowmick, Olga Volpert, Nader Sheibani; Small PEDF-derived peptides mitigate choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2019;60(9):355.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Abnormal migration and proliferation of endothelial cells (EC) drive exudative AMD, diabetic retinopathy and retinopathy of prematurity with adverse effects on vision. Decreased levels of endogenous inhibitors of angiogenesis, including pigment epithelium derived factor (PEDF), make a significant contribution to these pathologies. A PEDF surface helical 34-mer peptide carries its antiangiogenic activity. PEDF peptides of 18-34 amino acids show this activity but are too large for therapeutic use. Here we sought smaller peptides derived from the 34-mer, having potent anti-angiogenic activity, to mitigate choroidal neovascularization (CNV).
Truncation of the PEDF 34-mer led to identification of anti-angiogenic smaller peptides. In addition, further changes identified the N-terminal dicarboxylic acid (DCA) modified octa- and nonapeptides, where DCA charge compensation by substitution of Asn for an Asp residue, optimized apoptotic response in activated EC. Two potent small peptides (8-mer, 9-mer) were delivered by intravitreal (IVT) injection of mice subjected to laser-induced CNV. The degrees of neovascularization was assessed by immunostaining of flatmounts with ICAM-2 antibody and measurements of area of neovascularization. The ocular safety was also assessed by electroretinography (ERG) and histological evaluation in mice and rabbits.
A single IVT injection of 2-4 nmoles of either peptide, 2-5 days prior to laser treatment, resulted in a significant decrease in CNV at day 14. The smaller peptide (zero net-charge) was also active when administered as bid eye drops. No inflammation or ERG effects were observed. In addition, the peptides at 100 µM, were not cytotoxic to various retinal cell lines. Histopathology was negative in rabbit eyes injected with 300 µg of either peptide.
A small anti-angiogenic pharmacophore was defined within the PEDF sequence (Y-D-L-Y-R-V). New modifications (adipic-X-Y-N-L-Y-R-V…) yielded practical, CNV-mitigating peptides that are potently anti-angiogenic, without direct neutralization of vascular endothelial growth factor.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only