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Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.

ABSTRACT: 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.

SUBMITTER: Han SP

PROVIDER: S-EPMC8789579 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.

Han Si-Ping SP Scherer Lisa L Gethers Matt M Salvador Ane M AM Salah Marwa Ben Haj MBH Mancusi Rebecca R Sagar Sahil S Hu Robin R DeRogatis Julia J Kuo Ya-Huei YH Marcucci Guido G Das Saumya S Rossi John J JJ Goddard William A WA

Molecular therapy. Nucleic acids 20220103

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 ...[more]

PMID: 35116191

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Dataset Information

Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.

Publications

Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.

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