Robust, Durable Gene Activation In Vivo via mRNA-Encoded Activators

Programmable control of gene expression via nuclease-null Cas9 fusion proteins has enabled the engineering of cellular behaviors. Here, both transcriptional and epigenetic gene activation via synthetic mRNA and lipid nanoparticle delivery was demonstrated in vivo. These highly efficient delivery str...

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Bibliographic Details
Published inACS nano Vol. 16; no. 4; pp. 5660 - 5671
Main Authors Beyersdorf, Jared P, Bawage, Swapnil, Iglesias, Nahid, Peck, Hannah E, Hobbs, Ryan A, Wroe, Jay A, Zurla, Chiara, Gersbach, Charles A, Santangelo, Philip J
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 26.04.2022
Subjects
CRISPR-Associated Protein 9 - genetics
CRISPR-Cas Systems
Liposomes
RNA, Messenger - genetics
Transcriptional Activation
CRISPR
lipid nanoparticle
nonviral
dCas9
mRNA
in vivo
gene activation
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Summary:Programmable control of gene expression via nuclease-null Cas9 fusion proteins has enabled the engineering of cellular behaviors. Here, both transcriptional and epigenetic gene activation via synthetic mRNA and lipid nanoparticle delivery was demonstrated in vivo. These highly efficient delivery strategies resulted in high levels of activation in multiple tissues. Finally, we demonstrate durable gene activation in vivo via transient delivery of a single dose of a gene activator that combines VP64, p65, and HSF1 with a SWI/SNF chromatin remodeling complex component SS18, representing an important step toward gene-activation-based therapeutics. This induced sustained gene activation could be inhibited via mRNA-encoded AcrIIA4, further improving the safety profile of this approach.
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ISSN:1936-0851
1936-086X
1936-086X
DOI:10.1021/acsnano.1c10631