Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration.

Autor:	Gnanaguru G; Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA., Wagschal A; Massachusetts General Hospital Center for Cancer Research, Department of Cell Biology, Harvard Medical School, Charlestown, MA 02129, USA., Oh J; Massachusetts General Hospital Center for Cancer Research, Department of Cell Biology, Harvard Medical School, Charlestown, MA 02129, USA., Saez-Torres KL; Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA., Li T; Saha Cardiovascular Research Center and Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA., Temel RE; Saha Cardiovascular Research Center and Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA., Kleinman ME; Department of Ophthalmology and Visual Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Näär AM; Massachusetts General Hospital Center for Cancer Research, Department of Cell Biology, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: naar@berkeley.edu., D'Amore PA; Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: patricia_damore@meei.harvard.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Jul 07; Vol. 29 (7), pp. 2281-2293. Date of Electronic Publication: 2021 Mar 17.
DOI:	10.1016/j.ymthe.2021.03.014
Abstrakt:	Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expression of the miR-33 target ATP-binding cassette transporter (ABCA1), a cholesterol efflux pump genetically linked to AMD, declined reciprocally in the RPE with age. In accord, miR-33 modulated ABCA1 expression and cholesterol efflux in human RPE cells. Subcutaneous delivery of miR-33 antisense oligonucleotides (ASO) to aging mice and non-human primates fed a Western-type high fat/cholesterol diet resulted in increased ABCA1 expression, decreased cholesterol accumulation, and reduced immune cell infiltration in the RPE cell layer, accompanied by decreased pathological changes to RPE morphology. These findings suggest that miR-33 targeting may decrease cholesterol deposition and ameliorate AMD initiation and progression. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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