RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors.

ABSTRACT: CRISPR-Cas9 transcriptional repressors have emerged as robust tools for disrupting gene regulation in vitro but have not yet been adapted for systemic delivery in adult animal models. Here we describe a Staphylococcus aureus Cas9-based repressor (dSaCas9^KRAB) compatible with adeno-associated viral (AAV) delivery. To evaluate dSaCas9^KRAB efficacy for gene silencing in vivo, we silenced transcription of Pcsk9, a regulator of cholesterol levels, in the liver of adult mice. Systemic administration of a dual-vector AAV8 system expressing dSaCas9^KRAB and a Pcsk9-targeting guide RNA (gRNA) results in significant reductions of serum Pcsk9 and cholesterol levels. Despite a moderate host response to dSaCas9^KRAB expression, Pcsk9 repression is maintained fo

SUBMITTER: Thakore PI 

PROVIDER: S-EPMC5920046 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature