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In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering
Nature
(2026) Cite this article
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Circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins are leading risk factors for atherosclerotic cardiovascular disease1. Despite several approved lipid-lowering medications, most patients fail to achieve target lipid levels under the chronic care treatment model2,3. Here, we describe a potential single-course treatment in which an infusion of guide RNA and mRNA encoding a CRISPR adenine base editor—encapsulated within a GalNAc–lipid nanoparticle—leads to durable, liver-selective inactivation of angiopoietin-like 3 (ANGPTL3), a known driver of increased LDL-C and triglyceride concentrations. Analyses in human liver cells in vitro confirmed that the base editor introduces a DNA base-pair change at the target ANGPTL3 locus with no detectable off-target editing at any of approximately 3000 candidate sites or treatment-related structural variants. Targeted ANGPTL3 inactivation in nonhuman primates was well-tolerated and led to a > 90% mean reduction in circulating ANGPTL3 protein, with durability confirmed out to 3 years following a single dose. In mouse and nonhuman primate models of hyperlipidemia, gene inactivation was associated with reductions of approximately 40 to 50% in LDL-C and 50 to 70% in triglycerides. These results provided the scientific foundation for initiation of an ongoing first-in-human clinical trial in patients with refractory hyperlipidemia syndromes.
Verve Therapeutics, Inc. (a wholly owned subsidiary of Eli Lilly and Company), Boston, MA, USA
Taiji Mizoguchi, Jamie E. DeNizio, Alexandra C. Chadwick, Anne Marie Mazzola, Maxwell P. Brown, Shashank Mishra, Manashree Damle, Yuri Matsumoto, Victoria Neang, Ryan Garrity, Manini Mantri, Joy Oshoname Olorife, Hui-Ting Hsu, Vian Peshdary, Estela Shabani, John D. Ganey, Ryan Santos, Anthony Federico, Sara P. Garcia, Pengying Hao, Yue Wu, Zachary Glass, Lisa N. Kasiewicz, Caroline Summers, Athul Sanjeev, Kui Wang, Steven D. Briscoe, Christopher J. Cheng, Ellen Rohde, Joseph Biedenkapp, Victor Farutin, Andrew M. Bellinger, Sekar Kathiresan, Troy Lister, Kallanthottathil G. Rajeev, Richard G. Lee & Amit V. Khera
Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Mizoguchi, T., DeNizio, J.E., Chadwick, A.C. et al. In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering.
Nature (2026). https://doi.org/10.1038/s41586-026-11233-9