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

Gopalan Gnanaguru, Alexandre Wagschal, Justin Oh, Kahira L. Saez-Torres, Tong Li, Ryan E. Temel, Mark E. Kleinman, Anders M. Näär, Patricia A. D'Amore

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)2281-2293
Number of pages13
JournalMolecular Therapy
Issue number7
StatePublished - Jul 7 2021

Bibliographical note

Publisher Copyright:
© 2021 The American Society of Gene and Cell Therapy


  • ABCA1
  • age-related macular degeneration
  • cholesterol
  • geographic atrophy
  • inflammation
  • microRNA
  • retinal pigment epithelial cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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