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

doi:10.1016/j.ymthe.2021.03.014

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 journal › Article › peer-review

6 Scopus citations

Abstract

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 language	English
Pages (from-to)	2281-2293
Number of pages	13
Journal	Molecular Therapy
Volume	29
Issue number	7
DOIs	https://doi.org/10.1016/j.ymthe.2021.03.014
State	Published - Jul 7 2021

Bibliographical note

Funding Information:
Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA. G.G. performed all the in vitro studies and gene expression studies, prepared mouse and NHP retinal sections for immunostaining, analyzed data, and wrote the manuscript. A.W. designed and performed mouse LNA ASO studies, measured miRNA levels, performed serum lipid profiles in mice, and assisted G.G. with experimental design. J.O. assisted A.W. with all the in vivo studies. K.L.S.-T. assisted G.G. with immunostaining and masked analysis of RPE cell size measurements. T.L. performed NHP studies. R.E.T. designed and oversaw NHP studies. M.E.K. taught enucleation of NHP eyes to T.L. and assisted with RPE sample collection for histology and gene expression studies. A.M.N. and P.A.D. supervised the overall study and assisted with data analysis and manuscript preparation. The authors declare no competing interests.

Funding Information:
Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA.

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

Keywords

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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10.1016/j.ymthe.2021.03.014

Cite this

@article{7904050d84bb454cbea6bf3a4760924a,

title = "Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration",

abstract = "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.",

keywords = "ABCA1, age-related macular degeneration, cholesterol, geographic atrophy, inflammation, microRNA, retinal pigment epithelial cells",

author = "Gopalan Gnanaguru and Alexandre Wagschal and Justin Oh and Saez-Torres, {Kahira L.} and Tong Li and Temel, {Ryan E.} and Kleinman, {Mark E.} and N{\"a}{\"a}r, {Anders M.} and D'Amore, {Patricia A.}",

note = "Funding Information: Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA. G.G. performed all the in vitro studies and gene expression studies, prepared mouse and NHP retinal sections for immunostaining, analyzed data, and wrote the manuscript. A.W. designed and performed mouse LNA ASO studies, measured miRNA levels, performed serum lipid profiles in mice, and assisted G.G. with experimental design. J.O. assisted A.W. with all the in vivo studies. K.L.S.-T. assisted G.G. with immunostaining and masked analysis of RPE cell size measurements. T.L. performed NHP studies. R.E.T. designed and oversaw NHP studies. M.E.K. taught enucleation of NHP eyes to T.L. and assisted with RPE sample collection for histology and gene expression studies. A.M.N. and P.A.D. supervised the overall study and assisted with data analysis and manuscript preparation. The authors declare no competing interests. Funding Information: Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA. Publisher Copyright: {\textcopyright} 2021 The American Society of Gene and Cell Therapy",

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AU - Wagschal, Alexandre

AU - Oh, Justin

AU - Saez-Torres, Kahira L.

AU - Li, Tong

AU - Temel, Ryan E.

AU - Kleinman, Mark E.

AU - Näär, Anders M.

AU - D'Amore, Patricia A.

N1 - Funding Information: Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA. G.G. performed all the in vitro studies and gene expression studies, prepared mouse and NHP retinal sections for immunostaining, analyzed data, and wrote the manuscript. A.W. designed and performed mouse LNA ASO studies, measured miRNA levels, performed serum lipid profiles in mice, and assisted G.G. with experimental design. J.O. assisted A.W. with all the in vivo studies. K.L.S.-T. assisted G.G. with immunostaining and masked analysis of RPE cell size measurements. T.L. performed NHP studies. R.E.T. designed and oversaw NHP studies. M.E.K. taught enucleation of NHP eyes to T.L. and assisted with RPE sample collection for histology and gene expression studies. A.M.N. and P.A.D. supervised the overall study and assisted with data analysis and manuscript preparation. The authors declare no competing interests. Funding Information: Supported by the NIH National Eye Institute core grant P30EY003790 (P.A.D.), the Grimshaw-Gudewicz Charitable Foundation for AMD Research (P.A.D.), NIH grant R01 HL111932 (R.E.T.), the Stein Innovation Award from the Research to Prevent Blindness Foundation (A.M.N.), and an MGH Research Scholar Award (A.M.N.). We would like to thank Sierra Schlicht and Courtney Burkett and the Temel Lab, Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA, for technical assistance; Marcelo Cicconet, Department of Cell Biology, Harvard Medical School, Boston, MA, USA, for assistance with RPE image analysis; and Philip Seifert, morphology core, Schepens Eye Research Institute of Mass Eye and Ear, Boston, MA, USA. Publisher Copyright: © 2021 The American Society of Gene and Cell Therapy

PY - 2021/7/7

Y1 - 2021/7/7

N2 - 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.

AB - 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.

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KW - geographic atrophy

KW - inflammation

KW - microRNA

KW - retinal pigment epithelial cells

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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