Nature Biotechnology：周昌阳/孙怡迪/谢峻团队开发新型表观编辑器，单次给药即可高效、长效降血脂

Core Viewpoint - Gene editing technologies, such as CRISPR/Cas9 and next-generation base editing, are powerful tools for correcting pathogenic genes by permanently altering DNA sequences. However, ensuring the avoidance of unintended permanent changes in complex human environments remains a critical focus for broader clinical applications. In this context, epigenetic editing has gained attention as a complementary strategy, allowing precise regulation of gene expression without altering DNA sequences, thus providing new safety perspectives for gene therapy [3][4]. Summary by Sections Epigenetic Editing Potential - Zinc finger proteins and dCas9-based epigenetic editing therapies have shown significant potential, successfully inhibiting PCSK9 expression in mouse and non-human primate models, leading to effective reductions in blood cholesterol levels. PCSK9 is a key protein regulating "bad cholesterol" (LDL-C), making its inhibition an important strategy for cardiovascular disease prevention and treatment [4]. Challenges in Epigenetic Editing - The core challenge of epigenetic editing technology is maintaining long-term stability of the regulatory effects. Epigenetic modifications are dynamically reversible, and artificially established modifications may be diluted or reset during cell division. Current research has limited optimization of editing tools, primarily focusing on DNA methylation mechanisms. Systematic optimization and understanding of the long-lasting molecular mechanisms are essential for advancing this technology from laboratory to clinical applications [4]. Research Breakthroughs - A study published in Nature Biotechnology by teams from the Chinese Academy of Sciences and Anhui Medical University developed optimized epigenetic regulators for durable gene silencing, specifically targeting PCSK9 in non-human primates. The research demonstrated a significantly improved new editing tool with higher delivery efficiency and efficacy compared to existing systems [5][6]. EpiReg-T Development - The research team systematically screened different components and structures of epigenetic editors in mouse models, leading to the development of two superior versions: EpiReg-C based on dCas9 and EpiReg-T based on TALE. EpiReg-T exhibited a strong dose sensitivity, achieving significant suppression of PCSK9 at lower doses, validated in non-human primate models [7][8]. Long-term Efficacy and Safety - EpiReg-T was used for long-term validation, showing stable PCSK9 suppression even after liver cell regeneration. The epigenetic suppression demonstrated a reversible safety feature, allowing restoration of initial expression levels with an activating tool. In non-human primate experiments, a single high dose of EpiReg-T achieved approximately 90% PCSK9 suppression and about 60% reduction in "bad cholesterol," with effects remaining stable over 343 days [10][11]. Molecular Mechanisms - The study revealed that EpiReg-T established two suppressive "marks"—DNA methylation and histone H3K27e3 modification—while significantly downregulating various transcriptional activation modifications. Importantly, no significant off-target effects were observed, confirming the high targeting precision of EpiReg-T even at saturation doses [11][12]. Conclusion - The research successfully developed a highly efficient, durable, and specific epigenetic editor, EpiReg-T, demonstrating "one-time administration, long-term efficacy" in lipid-lowering effects in non-human primates. This study paves the way for the clinical application of epigenetic gene therapy [12].