Article ; Online: Engineered Circular RNA Sponges Act as miRNA Inhibitors to Attenuate Pressure Overload-Induced Cardiac Hypertrophy.
Molecular therapy : the journal of the American Society of Gene Therapy
2020 Volume 28, Issue 6, Page(s) 1506–1517
Abstract: 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- ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Base Sequence ; Binding Sites ; Cardiomegaly/diagnosis ; Cardiomegaly/etiology ; Cardiomegaly/physiopathology ; Cardiomegaly/therapy ; Disease Models, Animal ; Gene Expression Regulation ; Gene Transfer Techniques ; Genetic Engineering ; Genetic Therapy/methods ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Heart Function Tests ; Mice ; MicroRNAs/administration & dosage ; MicroRNAs/chemistry ; MicroRNAs/genetics ; RNA Interference ; RNA Stability ; RNA, Circular/administration & dosage ; RNA, Circular/chemistry ; RNA, Circular/genetics |
| Chemical Substances | MicroRNAs ; RNA, Circular |
| Language | English |
| Publishing date | 2020-04-14 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2010592-7 |
| ISSN | 1525-0024 ; 1525-0016 |
| ISSN (online) | 1525-0024 |
| ISSN | 1525-0016 |
| DOI | 10.1016/j.ymthe.2020.04.006 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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