Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries

The anti-inflammatory molecule annexin A1 (ANXA1) determines the ultimate fate of retinal ganglion cell (RGC) in glaucoma. Cytoplasmic and extracellular ANXA1 facilitate resolution of inflammation. However, the nuclear translocation of ANXA1 induces RGC apoptosis in a murine glaucoma model, and the...

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Main Authors: Jing Luo, Shengli Wang, Zhenlong Zhou, Yin Zhao
Format: Article
Language:English
Published: Elsevier 2021-03-01
Series:Molecular Therapy: Methods & Clinical Development
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2329050121000127
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spelling doaj-f30cdc8a06214ee4bc3d1232785076f52021-03-13T04:23:52ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-03-0120551558Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuriesJing Luo0Shengli Wang1Zhenlong Zhou2Yin Zhao3The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, ChinaThe First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, ChinaThe First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy, Jinan University, Guangzhou 510632, ChinaDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Corresponding author: Yin Zhao, Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.The anti-inflammatory molecule annexin A1 (ANXA1) determines the ultimate fate of retinal ganglion cell (RGC) in glaucoma. Cytoplasmic and extracellular ANXA1 facilitate resolution of inflammation. However, the nuclear translocation of ANXA1 induces RGC apoptosis in a murine glaucoma model, and the maintenance of ANXA1 secreted in the extracellular environments remains unclear. In this study, we found that intravitreal injection of the recombinant adenovirus vector (Ad)-ATP-binding cassette transporter A1 (ABCA1; carrying full-length ABCA1) improved RGC survival in the ischemia reperfusion (IR) mice model. Upregulation of ABCA1 maintained ANXA1 cytoplasmic location and reduced ANXA1 nuclear translocation, which is due to the decreased binding of ANXA1 with importin β. Moreover, we found that amino acids 903 to 1,344 of ABCA1 interacted with ANXA1 and decreased its nuclear localization. Importantly, intravitreal injection of adenovirus-associated viral (AAV) vector AAV8-ABCA1 (carrying 903 to 1,344 fragments of ABCA1) maintained ANXA1 cytoplasmic location and improved RGC survival in the IR mice model. Thus, overexpression of ABCA1 protects against RGC apoptosis by partially blocking ANXA1 nuclear translocation. This study puts forth a potential gene treatment strategy to prevent RGC apoptosis in glaucoma.http://www.sciencedirect.com/science/article/pii/S2329050121000127retinaretinal ganglion cellsRGCsischemia reperfusionannexin A1ABCA1
collection DOAJ
language English
format Article
sources DOAJ
author Jing Luo
Shengli Wang
Zhenlong Zhou
Yin Zhao
spellingShingle Jing Luo
Shengli Wang
Zhenlong Zhou
Yin Zhao
Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
Molecular Therapy: Methods & Clinical Development
retina
retinal ganglion cells
RGCs
ischemia reperfusion
annexin A1
ABCA1
author_facet Jing Luo
Shengli Wang
Zhenlong Zhou
Yin Zhao
author_sort Jing Luo
title Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
title_short Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
title_full Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
title_fullStr Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
title_full_unstemmed Ad- and AAV8-mediated ABCA1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
title_sort ad- and aav8-mediated abca1 gene therapy in a murine model with retinal ischemia/reperfusion injuries
publisher Elsevier
series Molecular Therapy: Methods & Clinical Development
issn 2329-0501
publishDate 2021-03-01
description The anti-inflammatory molecule annexin A1 (ANXA1) determines the ultimate fate of retinal ganglion cell (RGC) in glaucoma. Cytoplasmic and extracellular ANXA1 facilitate resolution of inflammation. However, the nuclear translocation of ANXA1 induces RGC apoptosis in a murine glaucoma model, and the maintenance of ANXA1 secreted in the extracellular environments remains unclear. In this study, we found that intravitreal injection of the recombinant adenovirus vector (Ad)-ATP-binding cassette transporter A1 (ABCA1; carrying full-length ABCA1) improved RGC survival in the ischemia reperfusion (IR) mice model. Upregulation of ABCA1 maintained ANXA1 cytoplasmic location and reduced ANXA1 nuclear translocation, which is due to the decreased binding of ANXA1 with importin β. Moreover, we found that amino acids 903 to 1,344 of ABCA1 interacted with ANXA1 and decreased its nuclear localization. Importantly, intravitreal injection of adenovirus-associated viral (AAV) vector AAV8-ABCA1 (carrying 903 to 1,344 fragments of ABCA1) maintained ANXA1 cytoplasmic location and improved RGC survival in the IR mice model. Thus, overexpression of ABCA1 protects against RGC apoptosis by partially blocking ANXA1 nuclear translocation. This study puts forth a potential gene treatment strategy to prevent RGC apoptosis in glaucoma.
topic retina
retinal ganglion cells
RGCs
ischemia reperfusion
annexin A1
ABCA1
url http://www.sciencedirect.com/science/article/pii/S2329050121000127
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AT shengliwang adandaav8mediatedabca1genetherapyinamurinemodelwithretinalischemiareperfusioninjuries
AT zhenlongzhou adandaav8mediatedabca1genetherapyinamurinemodelwithretinalischemiareperfusioninjuries
AT yinzhao adandaav8mediatedabca1genetherapyinamurinemodelwithretinalischemiareperfusioninjuries
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