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

被引：0

作者：

Tremblay, Frederic ^{[1
]}

Xiong, Qiang ^{[1
,4
]}

Shah, Shrijal S. ^{[1
,4
]}

Ko, Chih-Wei ^{[1
,4
]}

Kelly, Kenneth ^{[1
]}

Morrison, Mary S. ^{[1
]}

Giancarlo, Cristiana ^{[1
,4
]}

Ramirez, Ricardo N. ^{[1
,4
]}

Hildebrand, Erica M. ^{[1
,4
]}

Voytek, Sarah B. ^{[1
,4
]}

El Sebae, Gabriel K. ^{[1
]}

Wright, Shane H. ^{[1
,4
]}

Lofgren, Liam ^{[1
]}

Clarkson, Scott ^{[1
]}

Waters, Christine ^{[1
,4
]}

Linder, Samantha J. ^{[1
]}

Liu, Songlei ^{[1
,4
]}

Eom, Taesun ^{[1
,4
]}

Parikh, Shefal ^{[1
,4
]}

Weber, Yuki ^{[1
,4
]}

Martinez, Salette ^{[1
,4
]}

Malyala, Padma ^{[1
,4
]}

Abubucker, Sahar ^{[1
,4
]}

Friedland, Ari E. ^{[1
]}

Maeder, Morgan L. ^{[1
]}

Lombardo, Angelo ^{[2
,3
]}

Myer, Vic E. ^{[1
]}

Jaffe, Aron B. ^{[1
,5
]}

机构：

[1] Chroma Med, Boston, MA 02215 USA

[2] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, Milan, Italy

[3] Univ Vita Salute San Raffaele, Milan, Italy

[4] nChromaBio, Boston, MA USA

[5] curie Bio, Cambridge, MA USA

来源：

NATURE MEDICINE | 2025年

关键词：

SUBTILISIN/KEXIN TYPE 9; GENOMIC DNA; BASE; CRISPR; EFFICACY; DELIVERY; SAFETY; LIPIDS; LDL;

D O I：

10.1038/s41591-025-03508-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1329 / 1338

页数：22

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