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

ABSTRACT: 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.

SUBMITTER: Beyersdorf JP

PROVIDER: S-EPMC9047660 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Beyersdorf Jared P JP Bawage Swapnil S Iglesias Nahid N Peck Hannah E HE Hobbs Ryan A RA Wroe Jay A JA Zurla Chiara C Gersbach Charles A CA Santangelo Philip J PJ

ACS nano 20220331 4

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 VP6 ...[more]

PMID: 35357116

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