A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels
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.
Authors
- Suhag H Parikh (ORCID: https://orcid.org/0000-0002-6066-9852)
- Scott Clarkson
- Ari E. Friedland (ORCID: https://orcid.org/0000-0003-4983-1801)
- Lars Löfgren (ORCID: https://orcid.org/0000-0002-9207-1126)
- Cristiana Giancarlo
- Svati H. Shah (ORCID: https://orcid.org/0000-0002-3495-2830)
- Songlei Liu (ORCID: https://orcid.org/0000-0001-8607-8260)
- Erica M. Hildebrand (ORCID: https://orcid.org/0000-0001-7625-8997)
- C.M. Waters
- Angelo Lombardo (ORCID: https://orcid.org/0000-0001-8262-042X)
- Samantha J Linder (ORCID: https://orcid.org/0009-0007-6005-7913)
- Padma Malyala
- Aron B. Jaffe (ORCID: https://orcid.org/0000-0002-6220-0476)
- Sahar Abubucker (ORCID: https://orcid.org/0000-0002-5568-5129)
- Morgan L. Maeder (ORCID: https://orcid.org/0000-0001-9229-0479)
- Vic E. Myer (ORCID: https://orcid.org/0009-0008-6020-7536)
- Yvonne Weber (ORCID: https://orcid.org/0000-0002-0806-5592)
- Ricardo N. Ramírez (ORCID: https://orcid.org/0000-0002-1259-5406)
- Sarah B. Voytek
- Qiang Xiong (ORCID: https://orcid.org/0000-0001-7759-6736)
- José Simón Martínez-Castañeda (ORCID: https://orcid.org/0000-0002-8727-0307)
- Sarah Wright (ORCID: https://orcid.org/0000-0002-9539-3796)
- M Morrison
- Frédéric Tremblay
- Kenneth Kelly
- Chih‐Wei Ko
- Gabriel K El Sebae
- Taesun Eom
Institutions
- Biogen (United States) (US)
- Vita-Salute San Raffaele University (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Woman's Hospital (US)
- ChromaDex (United States) (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1038/s41591-025-03508-x
- Citations
- 58
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 46.75