A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels.

ABSTRACT: Epigenetic editing holds the promise of durable therapeutic effects by silencing disease-causing genes without changing the underlying DNA sequence. In this study, we designed an epigenetic editor to target human PCSK9 and thereby induce DNA methylation at this locus. A single administration of lipid nanoparticles encapsulating mRNA encoding this epigenetic editor was sufficient to drive near-complete silencing of human PCSK9 in transgenic mice. Silencing was durable for at least 1 year and was fully maintained after partial hepatectomy-induced liver regeneration. In addition, we showed reversibility of epigenetic editing in mice with previously silenced PCSK9 upon treatment with a targeted epigenetic activator designed to demethylate the PCSK9 locus. Notably, in cynomolgus monkeys, a sing

SUBMITTER: Tremblay F 

PROVIDER: S-EPMC12003160 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature