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

Yi Lu; Phillip W.L. Tai; Jianzhong Ai; Dominic J. Gessler; Qin Su; Xieyi Yao; Qiang Zheng; Phillip D. Zamore; Xun Xu; Guangping Gao

doi:10.1016/j.omtn.2017.12.019

Molecular Therapy: Nucleic Acids (Mar 2018)

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

Yi Lu,
Phillip W.L. Tai,
Jianzhong Ai,
Dominic J. Gessler,
Qin Su,
Xieyi Yao,
Qiang Zheng,
Phillip D. Zamore,
Xun Xu,
Guangping Gao

Affiliations

Yi Lu: Department 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, USA
Phillip W.L. Tai: 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
Jianzhong Ai: 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
Dominic J. Gessler: 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
Qin Su: 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
Xieyi Yao: Department 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
Qiang Zheng: Research and Development Center, Chengdu Kanghong Pharmaceuticals Group Co., Chengdu, Sichuan 610036, China
Phillip D. Zamore: RNA Therapeutics Institute, UMass Medical School, Worcester, MA 01605, USA
Xun Xu: Department 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.
Guangping Gao: 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.

DOI: https://doi.org/10.1016/j.omtn.2017.12.019
Journal volume & issue: Vol. 10
pp. 349 – 360

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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