Khirallah Jennifer, Bloomer Hanan, Wich Douglas, Huang Changfeng, Workman J Noah, Li Yamin, Newby Gregory A, Liu David R, Xu Qiaobing
Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.
School of Medicine and Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Mol Ther Nucleic Acids. 2025 Feb 15;36(2):102486. doi: 10.1016/j.omtn.2025.102486. eCollection 2025 Jun 10.
Cardiovascular disease (CVD) is the leading cause of death globally and is exacerbated by elevated blood levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). Existing approaches for decreasing blood lipid levels rely on daily medications, leading to poor patient adherence. Gene therapy represents a promising "one and done" strategy to durably reduce blood lipid levels. has emerged as a potential target for gene therapy, as naturally occurring loss-of-function variants are cardioprotective. Here, we use lipid nanoparticles to package and deliver CRISPR adenine base editors (ABEs), which enable gene knockout without requiring potentially harmful DNA double-strand breaks. We package ABE mRNA and a synthetic guide RNA targeted to disrupt an important splice site in , which we administered to mice intravenously. We achieved over 60% base editing in the liver and durable reductions in serum ANGPTL3, LDL-C, and TGs for at least 100 days. Notably, blood lipid levels remained low when mice were challenged with a high-fat high-cholesterol diet up to 191 days after therapy. These results provide a foundation for a potential one-and-done treatment for CVD.
心血管疾病（CVD）是全球主要的死亡原因，而低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TGs）的血液水平升高会加剧这种情况。现有的降低血脂水平的方法依赖于每日用药，导致患者依从性较差。基因治疗是一种有前景的“一次治疗，长期有效”策略，可持久降低血脂水平。由于天然存在的功能丧失变异具有心脏保护作用，因此已成为基因治疗的潜在靶点。在这里，我们使用脂质纳米颗粒来包装和递送CRISPR腺嘌呤碱基编辑器（ABE），其能够在不产生潜在有害DNA双链断裂的情况下实现基因敲除。我们包装了ABE mRNA和靶向破坏一个重要剪接位点的合成引导RNA，并将其静脉注射给小鼠。我们在肝脏中实现了超过60%的碱基编辑，并使血清血管生成素样蛋白3（ANGPTL3）、LDL-C和TGs持久降低至少100天。值得注意的是，在治疗后长达191天用高脂肪高胆固醇饮食对小鼠进行刺激时，血脂水平仍保持较低。这些结果为CVD的潜在一次性治疗提供了基础。
