A study published in Nature (DOI: 10.1038/s41586-024-07087-8) demonstrates the effectiveness of hit-and-run epigenome editing for durable and efficient gene silencing in vivo. The researchers targeted the Pcsk9 gene, which is involved in cholesterol homeostasis, using zinc-finger protein (ZFP)-based engineered transcriptional repressors (ETRs). In vitro screening identified ZFP-based ETRs as the most effective for silencing Pcsk9. A single administration of lipid nanoparticles (LNPs) loaded with ETR mRNAs reduced Pcsk9 levels by nearly 50% in mice for over a year. The silencing persisted even after liver regeneration, indicating the heritability of the epigenetic state. An improved design, the evolved engineered transcriptional repressor (EvoETR), combined multiple epigenetic repressive pathways, achieving similar efficiency to conventional gene editing without causing DNA breaks. The study shows that ETRs can induce durable epigenetic silencing in vivo, with EvoETR-8 demonstrating high specificity and efficiency. The results suggest that ETR-based epigenome editing could be a promising therapeutic approach for gene therapy, offering durable and specific gene silencing with reduced off-target effects. The study also highlights the potential of ETR technology for future applications in epigenetic therapy.A study published in Nature (DOI: 10.1038/s41586-024-07087-8) demonstrates the effectiveness of hit-and-run epigenome editing for durable and efficient gene silencing in vivo. The researchers targeted the Pcsk9 gene, which is involved in cholesterol homeostasis, using zinc-finger protein (ZFP)-based engineered transcriptional repressors (ETRs). In vitro screening identified ZFP-based ETRs as the most effective for silencing Pcsk9. A single administration of lipid nanoparticles (LNPs) loaded with ETR mRNAs reduced Pcsk9 levels by nearly 50% in mice for over a year. The silencing persisted even after liver regeneration, indicating the heritability of the epigenetic state. An improved design, the evolved engineered transcriptional repressor (EvoETR), combined multiple epigenetic repressive pathways, achieving similar efficiency to conventional gene editing without causing DNA breaks. The study shows that ETRs can induce durable epigenetic silencing in vivo, with EvoETR-8 demonstrating high specificity and efficiency. The results suggest that ETR-based epigenome editing could be a promising therapeutic approach for gene therapy, offering durable and specific gene silencing with reduced off-target effects. The study also highlights the potential of ETR technology for future applications in epigenetic therapy.