In a groundbreaking study, researchers have successfully demonstrated the potential for durable epigenetic silencing using programmable editors equipped with transcriptional repressors, showing promise for the treatment of human diseases. The study targeted the Pcsk9 gene expressed in hepatocytes, involved in cholesterol homeostasis. Zinc-finger proteins were found to be the most efficient DNA-binding platform for silencing mouse Pcsk9.

Through a single administration of lipid nanoparticles loaded with editors' mRNAs, circulating levels of PCSK9 were nearly halved in mice for almost a year. Remarkably, the epigenetic repressive marks and Pcsk9 silencing persisted even after liver regeneration, demonstrating the heritability of the installed epigenetic state. Enhancements in construct design led to the creation of an all-in-one configuration named evolved engineered transcriptional repressor (EvoETR), which successfully reduced PCSK9 levels in mice with high specificity, comparable to conventional gene editing, without causing DNA breaks.

This study paves the way for the development of innovative in vivo therapeutics based on epigenetic silencing, offering exciting possibilities in the realm of disease treatment.