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<p>Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (<i>PCSK9</i>) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (&gt;90%) and long-lasting (343 days) silencing of <i>PCSK9</i> in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.</p>

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Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • Shaoshuai Mao,
  • Wenbo Peng,
  • Zhengyan Feng,
  • Yang Chen,
  • Jing Sun,
  • Haiting Chen,
  • Pengcheng Wang,
  • Pinzheng Huang,
  • Junzheng Zhao,
  • Leilei Wu,
  • Yifan Wang,
  • Junjian Liu,
  • Hao Luo,
  • Ying Zang,
  • Changqing Yang,
  • Xue Qiao,
  • Zhiwei Lu,
  • Hongjun Wu,
  • Mingjie Chen,
  • Di Sun,
  • Jun Xie,
  • Yidi Sun,
  • Changyang Zhou

摘要

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.