期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 27, 期 -, 页码 797-809出版社
CELL PRESS
DOI: 10.1016/j.omtn.2021.12.039
关键词
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资金
- NSF [NSF EFRI-ODISSEI 1332411, CMMI-SNM 1120890]
- NIH [R35HL150807]
- Margaret E. Early Medical Research Trust
- Gehr Family Center for Leukemia Research
This study achieved the development of siRNA pro-drugs based on nucleic acid switches, which selectively interfere with target genes through specific RNA biomarkers. It demonstrated potential clinical applications in rat cardiomyocytes, providing a new avenue for the treatment of heart diseases.
Since Paul Ehrlich's introduction of the magic bullet concept in 1908, drug developers have been seeking new ways to target drug activity to diseased cells while limiting effects on normal tissues. In recent years, it has been proposed that coupling riboswitches capable of detecting RNA biomarkers to small interfering RNAs (siRNAs) to create siRNA pro-drugs could selectively activate RNA interference (RNAi) activity in specific cells. However, this concept has not been achieved previously. We report here that we have accomplished this goal, validating a simple and programmable new design that functions reliably in mammalian cells. We show that these conditionally activated siRNAs (Cond-siRNAs) can switch RNAi activity against different targets between clearly distinguished OFF and ON states in response to different cellular RNA biomarkers. Notably, in a rat cardiomyocyte cell line (H9C2), one version of our construct demonstrated biologically meaningful inhibition of a heart-disease-related target gene protein phosphatase 3 catalytic subunit alpha (PPP3CA) in response to increased expression of the pathological marker atrial natriuretic peptide (NPPA) messenger RNA (mRNA). Our results demonstrate the ability of synthetic riboswitches to regulate gene expression in mammalian cells, opening a new path for development of programmable siRNA pro-drugs.
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