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Development and Optimization of Logic Gated Small Interfering RNAs for Operation Inside Mammalian Cells

Han, Si-Ping and Scherer, Lisa and Salvador-Garicano, Ane M. and Gethers, Matt and Haj-Salah, Marwa Ben and Mancusi, Rebecca and Sagar, Sahil and Hu, Robin and DeRogatis, Julia and Kuo, Ya-Huei and Marcucci, Guido and Das, Saumya and Rossi, John and Goddard, William A. (2020) Development and Optimization of Logic Gated Small Interfering RNAs for Operation Inside Mammalian Cells. Molecular Therapy, 28 (4). p. 112. ISSN 1525-0016. doi:10.1016/j.ymthe.2020.04.019.

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In 1900, Paul Ehrlich put forth the concept of a pharmacologic “magic bullet”, a combination of a disease selective chemical agent conjugated to a non-selective toxin that could target drug activity to disease causing cells without harming healthy tissues in the body. For the past two decades, various researchers in DNA and RNA nanotechnology have proposed ideas for riboswitch regulated magic bullets in which the activities of oligonucleotide drugs are switched ON or OFF according to the presence or absence of specific biomarkers in tissues or cells. Although elegant in concept, practical implementation of these “logical therapeutics” for mammalian cells has proven elusive. We have now developed a conditionally activated small interfering RNA (Cond-siRNA) in which an RNA sensor regulates the RNAi activity of a conjugated siRNA post-transfection into mammalian cells. The sensor switches ON RNAi activity when it base-pairs to an RNA transcript from a designated “trigger gene”. In cells without trigger gene expression, the sensor keeps RNAi activity OFF. The identities of the trigger and target genes are encoded by two entirely independent, easily programmable RNA sequences, giving the Cond-siRNAs the ability to target a specific population of cells for the silencing of an arbitrary gene. We will present experimental data for Cond-siRNAs with different trigger and target gene combinations in different mammalian cell lines, explain the design principles and optimizations that enable easy programmability and correct functioning in mammalian cells, and demonstrate an early example of therapeutic application development in the treatment of cardiac hypertrophy. As small, chemically modified, unimolecular RNA complexes, Cond-siRNAs are compatible with existing methods of siRNA delivery and practical for development into clinically viable RNAi drugs. By making possible post-delivery targeting of RNAi activity to specific populations of disease driving cells, they could enable paradigm shifting development of RNAi drugs that can safely target pleiotropic genes whose dysregulated activities drive the progression of many chronic diseases lacking effective treatments today.

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Han, Si-Ping0000-0002-2213-4953
Goddard, William A.0000-0003-0097-5716
Additional Information:© 2020 American Society of Gene & Cell Therapy. Available online 28 April 2020.
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Issue or Number:4
Record Number:CaltechAUTHORS:20200604-141204861
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Official Citation:2020 ASGCT Annual Meeting Abstracts, Molecular Therapy, Volume 28, Issue 4, Supplement 1, 2020, Pages 1-592, ISSN 1525-0016, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103698
Deposited By: Tony Diaz
Deposited On:04 Jun 2020 21:25
Last Modified:16 Nov 2021 18:24

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