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

JOURNAL OF CONTROLLED RELEASE

卷:283

Article

Sreekumar, Parameswaran G.¹  Li, Zhe²  Wang, Wan²  Spee, Christine³  Hinton, David R.^3,4  Kannan, Ram¹  MacKay, J. Andrew^2,3,5 

[1] Doheny Eye Inst, Arnold & Mabel Beckman Macular Res Ctr, Los Angeles, CA 90033 USA

[2] Univ Southern Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, 1985 Zonal Ave, Los Angeles, CA 90089 USA

[3] Univ Southern Calif, Keck Sch Med, USC Roski Eye Inst, Dept Ophthalmol, Los Angeles, CA 90033 USA

[4] Univ Southern Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

[5] Univ Southern Calif, Viterbi Sch Engn, Dept Biomed Engn, Los Angeles, CA 90033 USA

关键词: Elastin-like polypeptides;    Geographic atrophy;    alpha B crystallin;    RPE cell death;    Retinal degeneration;    NaIO3;   

DOI  :  10.1016/j.jconrel.2018.05.014

来源: Elsevier

【 摘 要 】

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 alpha B 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. alpha B 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.

【 授权许可】

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