Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.ymthe.2020.04.006
Title: Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy
Authors: Lavenniah, Annadoray
Tuan, Danh Anh Luu 
Li, Yiqing Peter 
Lim, Tingsen Benson 
Jiang, Jianming 
Ackers-Johnson, Matthew 
Foo, Roger 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
MICRORNA SPONGES
IN-VIVO
BIOGENESIS
EXPRESSION
PREDICTION
INTRON
HEART
AAV
Issue Date: 3-Jun-2020
Publisher: CELL PRESS
Citation: Lavenniah, Annadoray, Tuan, Danh Anh Luu, Li, Yiqing Peter, Lim, Tingsen Benson, Jiang, Jianming, Ackers-Johnson, Matthew, Foo, Roger (2020-06-03). Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy. MOLECULAR THERAPY 28 (6) : 1506-1517. ScholarBank@NUS Repository. https://doi.org/10.1016/j.ymthe.2020.04.006
Abstract: © 2020 The Author(s) Circular RNAs (circRNAs) sequester microRNAs (miRNAs) and repress their endogenous activity. We hypothesized that artificial circRNA sponges (circmiRs) can be constructed to target miRNAs therapeutically, with a low dosage requirement and extended half-lives compared to current alternatives. This could present a new treatment approach for critical global pathologies, including cardiovascular disease. Here, we constructed a circmiR sponge to target known cardiac pro-hypertrophic miR-132 and -212. Expressed circmiRs competitively inhibited miR-132 and -212 activity in luciferase rescue assays and showed greater stability than linear sponges. A design containing 12 bulged binding sites with 12 nucleotides spacing was determined to be optimal. Adeno-associated viruses (AAVs) were used to deliver circmiRs to cardiomyocytes in vivo in a transverse aortic constriction (TAC) mouse model of cardiac disease. Hypertrophic disease characteristics were attenuated, and cardiac function was preserved in treated mice, demonstrating the potential of circmiRs as novel therapeutic tools. Subsequently, group I permutated intron-exon sequences were used to directly synthesize exogenous circmiRs, which showed greater in vitro efficacy than the current gold standard antagomiRs in inhibiting miRNA function. Engineered circRNAs thus offer exciting potential as future therapeutics.
Source Title: MOLECULAR THERAPY
URI: https://scholarbank.nus.edu.sg/handle/10635/171691
ISSN: 1525-0016
1525-0024
DOI: 10.1016/j.ymthe.2020.04.006
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