Category: Biologics Discovery
The creation of DNA double-strand breaks (DSBs) has become a central approach to facilitate genome editing. In the meantime, concerns about unwanted mutations caused by DSBs have never been alleviated, particularly for applying genome editing in clinical therapeutics. CRISPR/Cas9 system has been repurposed to enable target gene activation, which allows controlling endogenous gene regulation without creating DSBs. However, in vivo implementation of these gain-of-function systems has proven challenging. Here we report a robust system for in vivo activation of endogenous target genes with trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat several disease mouse models. Our results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to observable phenotypic changes, and ameliorate disease symptoms, thus opening new avenues for developing targeted epigenetic therapies against human diseases.
Hsin-Kai Liao– Postdoc, Salk Institute, San Diego, California