Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice

Charleen Hunt, Suzanne A. Hartford, Derek White, Evangelos Pefanis, Timothy Hanna, Clarissa Herman, Jarrell Wiley, Heather Brown, Qi Su, Yurong Xin, Dennis Voronin, Hien Nguyen, Judith Altarejos, Keith Crosby, Jeffery Haines, Sarah Cancelarich, Meghan Drummond, Sven Moller-Tank, Ryan Malpass, Jacqueline Buckley, Maria Pilar Molina-Portela, Gustavo Droguett, David Frendewey, Eric Chiao, Brian Zambrowicz and Guochun Gong ()
Additional contact information
Charleen Hunt: Regeneron Pharmaceuticals, Inc.
Suzanne A. Hartford: Regeneron Pharmaceuticals, Inc.
Derek White: Regeneron Pharmaceuticals, Inc.
Evangelos Pefanis: Regeneron Pharmaceuticals, Inc.
Timothy Hanna: Regeneron Pharmaceuticals, Inc.
Clarissa Herman: Regeneron Pharmaceuticals, Inc.
Jarrell Wiley: Regeneron Pharmaceuticals, Inc.
Heather Brown: Regeneron Pharmaceuticals, Inc.
Qi Su: Regeneron Pharmaceuticals, Inc.
Yurong Xin: Regeneron Pharmaceuticals, Inc.
Dennis Voronin: Regeneron Pharmaceuticals, Inc.
Hien Nguyen: Regeneron Pharmaceuticals, Inc.
Judith Altarejos: Regeneron Pharmaceuticals, Inc.
Keith Crosby: Regeneron Pharmaceuticals, Inc.
Jeffery Haines: Regeneron Pharmaceuticals, Inc.
Sarah Cancelarich: Regeneron Pharmaceuticals, Inc.
Meghan Drummond: Regeneron Pharmaceuticals, Inc.
Sven Moller-Tank: Regeneron Pharmaceuticals, Inc.
Ryan Malpass: Regeneron Pharmaceuticals, Inc.
Jacqueline Buckley: Regeneron Pharmaceuticals, Inc.
Maria Pilar Molina-Portela: Regeneron Pharmaceuticals, Inc.
Gustavo Droguett: Regeneron Pharmaceuticals, Inc.
David Frendewey: Regeneron Pharmaceuticals, Inc.
Eric Chiao: Regeneron Pharmaceuticals, Inc.
Brian Zambrowicz: Regeneron Pharmaceuticals, Inc.
Guochun Gong: Regeneron Pharmaceuticals, Inc.

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract CRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.

Date: 2021
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DOI: 10.1038/s41467-021-22932-4

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