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 single administration of the epigenetic editor potently and durably decreased circulating PCSK9 protein levels by approximately 90% with concomitant reduction in low-density lipoprotein cholesterol levels by approximately 70%. These findings demonstrate the therapeutic potential of durable and reversible epigenetic editing in vivo and support the development of epigenetic editor–based treatment for hypercholesterolemia.
A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels / Tremblay, Frederic; Xiong, Qiang; Shah, Shrijal S; Ko, Chih-Wei; Kelly, Kenneth; Morrison, Mary S; Giancarlo, Cristiana; Ramirez, Ricardo N; Hildebrand, Erica M; Voytek, Sarah B; El Sebae, Gabriel K; Wright, Shane H; Lofgren, Liam; Clarkson, Scott; Waters, Christine; Linder, Samantha J; Liu, Songlei; Eom, Taesun; Parikh, Shefal; Weber, Yuki; Martinez, Salette; Malyala, Padma; Abubucker, Sahar; Friedland, Ari E; Maeder, Morgan L; Lombardo, Angelo; Myer, Vic E; Jaffe, Aron B. - In: NATURE MEDICINE. - ISSN 1546-170X. - 31:4(2025), pp. 1329-1338. [10.1038/s41591-025-03508-x]
A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels
Lombardo, Angelo;
2025-01-01
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 single administration of the epigenetic editor potently and durably decreased circulating PCSK9 protein levels by approximately 90% with concomitant reduction in low-density lipoprotein cholesterol levels by approximately 70%. These findings demonstrate the therapeutic potential of durable and reversible epigenetic editing in vivo and support the development of epigenetic editor–based treatment for hypercholesterolemia.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
