Mirna switches for rna-triggered control of rna interference

Abstract

Provided herein are methods, compositions and systems comprising synthetic nucleic acid molecules that enable inducible or conditional pri-miRNA processing, preferably in mammalian cells in vivo. Provided herein are synthetic nucleic acid molecules referred to as Orthogonal RNA Interference induced by Trigger RNA (ORIENTR) that switches between an inactive form and an active form upon interaction with one or more specific RNA-trigger molecules, which can be e.g., a synthetic RNA-trigger, or a disease-specific RNA signals, such as disease-specific mRNA, miRNA, or other cellular RNA products with sequences that characterize a disease state of a cell. The interaction between the RNA-trigger molecules and the ORIENTR is preferably mediated by hybridization, which exposes, facilitates the formation, and/or allows the formation of a correctly folded pri-miRNA scaffold substrate that can be processed by proteins of the RNAi pathway (such as Dicer), leading to RNAi-mediated repression of a target gene. Also provided herein are methods of using such ORIENTR molecules for the treatment or prevention of a disease in a subject, as well as detecting the presence or absence of a target RNA in a biological sample or in vivo.