Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs

Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs

Corneal neovascularization (NV) is the major sight-threatening pathology caused by angiogenic stimuli. Current drugs that directly target pro-angiogenic factors to inhibit or reverse the disease require multiple rounds of administration and have limited efficacies. Here, we identify potential anti-a...

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Main Authors: Yi Lu, Phillip W.L. Tai, Jianzhong Ai, Dominic J. Gessler, Qin Su, Xieyi Yao, Qiang Zheng, Phillip D. Zamore, Xun Xu, Guangping Gao
Format: Article
Language:English
Published: Elsevier 2018-03-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
adeno-associated virus
corneal neovascularization
gene therapy
microRNA
miR-204
Online Access:http://www.sciencedirect.com/science/article/pii/S2162253117303207
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language English
format Article
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author Yi Lu
Phillip W.L. Tai
Jianzhong Ai
Dominic J. Gessler
Qin Su
Xieyi Yao
Qiang Zheng
Phillip D. Zamore
Xun Xu
Guangping Gao
spellingShingle Yi Lu
Phillip W.L. Tai
Jianzhong Ai
Dominic J. Gessler
Qin Su
Xieyi Yao
Qiang Zheng
Phillip D. Zamore
Xun Xu
Guangping Gao
Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
Molecular Therapy: Nucleic Acids
adeno-associated virus
corneal neovascularization
gene therapy
microRNA
miR-204
author_facet Yi Lu
Phillip W.L. Tai
Jianzhong Ai
Dominic J. Gessler
Qin Su
Xieyi Yao
Qiang Zheng
Phillip D. Zamore
Xun Xu
Guangping Gao
author_sort Yi Lu
title Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
title_short Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
title_full Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
title_fullStr Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
title_full_unstemmed Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs
title_sort transcriptome profiling of neovascularized corneas reveals mir-204 as a multi-target biotherapy deliverable by raavs
publisher Elsevier
series Molecular Therapy: Nucleic Acids
issn 2162-2531
publishDate 2018-03-01
description Corneal neovascularization (NV) is the major sight-threatening pathology caused by angiogenic stimuli. Current drugs that directly target pro-angiogenic factors to inhibit or reverse the disease require multiple rounds of administration and have limited efficacies. Here, we identify potential anti-angiogenic corneal microRNAs (miRNAs) and demonstrate a framework that employs discovered miRNAs as biotherapies deliverable by recombinant adeno-associated viruses (rAAVs). By querying differentially expressed miRNAs in neovascularized mouse corneas induced by alkali burn, we have revealed 39 miRNAs that are predicted to target more than 5,500 differentially expressed corneal mRNAs. Among these, we selected miR-204 and assessed its efficacy and therapeutic benefit for treating injured corneas. Our results show that delivery of miR-204 by rAAV normalizes multiple novel target genes and biological pathways to attenuate vascularization of injured mouse cornea. Importantly, this gene therapy treatment alternative is efficacious and safe for mitigating corneal NV. Overall, our work demonstrates the discovery of potential therapeutic miRNAs in corneal disorders and their translation into viable treatment alternatives.
topic adeno-associated virus
corneal neovascularization
gene therapy
microRNA
miR-204
url http://www.sciencedirect.com/science/article/pii/S2162253117303207
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spelling doaj-c477d019d31e4780b69ad117ac5bd9182020-11-25T03:55:15ZengElsevierMolecular Therapy: Nucleic Acids2162-25312018-03-011034936010.1016/j.omtn.2017.12.019Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVsYi Lu0Phillip W.L. Tai1Jianzhong Ai2Dominic J. Gessler3Qin Su4Xieyi Yao5Qiang Zheng6Phillip D. Zamore7Xun Xu8Guangping Gao9Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China; Horae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, UMass Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, UMass Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Urology, Institute for Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaHorae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, UMass Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USAHorae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, UMass Medical School, Worcester, MA 01605, USADepartment of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, ChinaResearch and Development Center, Chengdu Kanghong Pharmaceuticals Group Co., Chengdu, Sichuan 610036, ChinaRNA Therapeutics Institute, UMass Medical School, Worcester, MA 01605, USADepartment of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China; Corresponding author: Xun Xu, Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai 200080, China.Horae Gene Therapy Center, UMass Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, UMass Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Urology, Institute for Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author: Guangping Gao, Horae Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, MA 01605, USA.Corneal neovascularization (NV) is the major sight-threatening pathology caused by angiogenic stimuli. Current drugs that directly target pro-angiogenic factors to inhibit or reverse the disease require multiple rounds of administration and have limited efficacies. Here, we identify potential anti-angiogenic corneal microRNAs (miRNAs) and demonstrate a framework that employs discovered miRNAs as biotherapies deliverable by recombinant adeno-associated viruses (rAAVs). By querying differentially expressed miRNAs in neovascularized mouse corneas induced by alkali burn, we have revealed 39 miRNAs that are predicted to target more than 5,500 differentially expressed corneal mRNAs. Among these, we selected miR-204 and assessed its efficacy and therapeutic benefit for treating injured corneas. Our results show that delivery of miR-204 by rAAV normalizes multiple novel target genes and biological pathways to attenuate vascularization of injured mouse cornea. Importantly, this gene therapy treatment alternative is efficacious and safe for mitigating corneal NV. Overall, our work demonstrates the discovery of potential therapeutic miRNAs in corneal disorders and their translation into viable treatment alternatives.http://www.sciencedirect.com/science/article/pii/S2162253117303207adeno-associated viruscorneal neovascularizationgene therapymicroRNAmiR-204

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