A Novel HDL-Mimetic Peptide HM-10/10 Protects RPE and Photoreceptors in Murine Models of Retinal Degeneration.

Feng Su,Christine Spee,Robin Farias-Eisner,Mo Wang,Steven Nusinowitz,Ram Kannan,David R Hinton,Srinivasa T Reddy,Caleb Ghione,Eric Barron,Eduardo Araujo

doi:10.3390/ijms20194807

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD. Oxidative stress plays a key role in the development of AMD. We generated a chimeric high-density lipoprotein (HDL), mimetic peptide named HM-10/10, with anti-oxidant properties and investigated its potential for the treatment of retinal disease using cell culture and animal models of RPE and photoreceptor (PR) degeneration. Treatment with HM-10/10 peptide prevented human fetal RPE cell death caused by tert-Butyl hydroperoxide (tBH)-induced oxidative stress and sodium iodate (NaIO3), which causes RPE atrophy and is a model of geographic atrophy in mice. We also show that HM-10/10 peptide ameliorated photoreceptor cell death and significantly improved retinal function in a mouse model of N-methyl-N-nitrosourea (MNU)-induced PR degeneration. Our results demonstrate that HM-10/10 protects RPE and retina from oxidant injury and can serve as a potential therapeutic agent for the treatment of retinal degeneration.

Highlights

Age-related macular degeneration (AMD) is characterized by progressive degeneration of the macular region of the retina resulting in loss of central vision
We examined the effect of HM-10/10 peptide on apoptosis in cell culture models
We first conducted dose response studies for HM-10/10 in human fetal RPE (hfRPE) cells (Supplemental Figure S1) and based on the results we used HM-10/10 at 10 μg/mL concentration in all the hfRPE cell culture experiments. hfRPE cells were cultured overnight in 0.5% serum containing DMEM medium and were either treated with HM-10/10 alone at 10 μg/mL or with 200 μM tert-Butyl hydroperoxide [8,9] alone or with a combination of tBH and HM-10/10 for 24 h

Summary

Introduction

Age-related macular degeneration (AMD) is characterized by progressive degeneration of the macular region of the retina resulting in loss of central vision. It causes damage to the central part of the retina, resulting in the loss of the light-sensitive tissue at the back of the eye. The key to reducing the AMD-related vision loss is to be able to initiate therapies that could halt or slow down the progression of AMD. High density lipoprotein (HDL) is an important mediator of lipid homeostasis. HDL mimetic peptides have shown efficacy in a number of animal models of disease and demonstrate properties that make them attractive as potential therapeutic agents [3,4,5,6,7]. We developed a novel chimeric high density lipoprotein; mimetic peptide named HM-10/10. The arginine-rich cationic domain of human apoE {([141–150] hApoE) L-R-K-L-R-K-R-L-L-R}, was added to an apoJ mimetic, named G * peptide {L-V-G-R-Q-L-E-E-F-L, corresponding to amino acids 113 to 122 in apoJ ([113,122] apoJ)}, to form HM-10/10 peptide containing 20 amino acids with the sequence of L-R-K-L-R-K-R-L-LR-L-V-G-R-Q-L-E-E-F-L

Methods

Results

Conclusion