Epigenome editing is emerging as powerful new strategy to silence gene expression without altering their primary DNA sequence. In this regard, we and others have previously shown that transient delivery of Engineered Transcriptional Repressors (ETRs) leads to efficient, long-term stable and specific epigenetic silencing of endogenous genes in both human and mouse cell lines and, more recently, in human primary T cells and iPSCs. The ETRs are chimeric proteins composed of a programmable DNA binding domain, such as CRISPR-Cas9 or ZFPs, fused to either one or more of the following epigenetic repressive domains: KRAB, the catalytic domain of DNMT3A and DNMT3L. Whether the ETR technology could program long-lasting gene silencing in vivo and at which extent remains unknown. During my talk, I will present our efforts to improve and characterize the technology towards the develop an in vivo hit-and-run epigenome editing approach for the treatment of familial and acquired hypercholesterolemia.