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<p>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 <i>PCSK9</i> 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 <i>PCSK9</i> 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 <i>PCSK9</i> upon treatment with a targeted epigenetic activator designed to demethylate the <i>PCSK9</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月10日

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  • Frederic Tremblay,
  • Qiang Xiong,
  • Shrijal S. Shah,
  • Chih-Wei Ko,
  • Kenneth Kelly,
  • Mary S. Morrison,
  • Cristiana Giancarlo,
  • Ricardo N. Ramirez,
  • Erica M. Hildebrand,
  • Sarah B. Voytek,
  • Gabriel K. El Sebae,
  • Shane H. Wright,
  • Liam Lofgren,
  • Scott Clarkson,
  • Christine Waters,
  • Samantha J. Linder,
  • Songlei Liu,
  • Taesun Eom,
  • Shefal Parikh,
  • Yuki Weber,
  • Salette Martinez,
  • Padma Malyala,
  • Sahar Abubucker,
  • Ari E. Friedland,
  • Morgan L. Maeder,
  • Angelo Lombardo,
  • Vic E. Myer,
  • Aron B. Jaffe

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.