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J Control Release. 2018 Aug 10;283:94-104. doi: 10.1016/j.jconrel.2018.05.014. Epub 2018 May 18.

Intra-vitreal αB crystallin fused to elastin-like polypeptide provides neuroprotection in a mouse model of age-related macular degeneration.

Author information

1
Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA 90033, USA.
2
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy of the University of Southern California, Los Angeles, CA 90089, USA.
3
Department Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
4
Department Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
5
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy of the University of Southern California, Los Angeles, CA 90089, USA; Department Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, Viterbi School of Engineering of the University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jamackay@usc.edu.

Abstract

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible central vision loss, and the primary site of AMD pathology is the retinal pigment epithelium (RPE). Geographic atrophy (GA) is an advanced form of AMD characterized by extensive RPE cell loss, subsequent degeneration of photoreceptors, and thinning of retina. This report describes the protective potential of a peptide derived from the αB crystallin protein using a sodium iodate (NaIO3) induced mouse model of GA. Systemic NaIO3 challenge causes degeneration of the RPE and neighboring photoreceptors, which have similarities to retinas of GA patients. αB crystallin is an abundant ocular protein that maintains ocular clarity and retinal homeostasis, and a small peptide from this protein (mini cry) displays neuroprotective properties. To retain this peptide for longer in the vitreous, mini cry was fused to an elastin-like polypeptide (ELP). A single intra-vitreal treatment by this crySI fusion significantly inhibits retinal degeneration in comparison to free mini cry. While mini cry is cleared from the eye with a mean residence time of 0.4 days, crySI is retained with a mean residence time of 3.0 days; furthermore, fundus photography reveals evidence of retention at two weeks. Unlike the free mini cry, crySI protects the RPE against NaIO3 challenge for at least two weeks after administration. CrySI also inhibits RPE apoptosis and caspase-3 activation and protects the retina from cell death up to 1-month post NaIO3 challenge. These results show that intra-ocular ELP-linked peptides such as crySI hold promise as protective agents to prevent RPE atrophy and progressive retinal degeneration in AMD.

KEYWORDS:

Elastin-like polypeptides; Geographic atrophy; NaIO(3); RPE cell death; Retinal degeneration; αB crystallin

PMID:
29778783
PMCID:
PMC6368441
[Available on 2019-08-10]
DOI:
10.1016/j.jconrel.2018.05.014

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