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In Vivo CRISPR Base Editing of <i>ANGPTL3</i> for Durable Lipid Lowering

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  • Article
  • Published:
  • Jamie E. DeNizio1,
  • Alexandra C. Chadwick1,
  • Anne Marie Mazzola1,
  • Maxwell P. Brown1,
  • Shashank Mishra1,
  • Manashree Damle1,
  • Yuri Matsumoto1,
  • Victoria Neang1,
  • Ryan Garrity1,
  • Manini Mantri1,
  • Joy Oshoname Olorife1,
  • Hui-Ting Hsu1,
  • Vian Peshdary1,
  • Estela Shabani1,
  • John D. Ganey1,
  • Ryan Santos1,
  • Anthony Federico1,
  • Sara P. Garcia1,
  • Pengying Hao1,
  • Yue Wu1,
  • Zachary Glass1,
  • Lisa N. Kasiewicz1,
  • Caroline Summers1,
  • Athul Sanjeev1,
  • Kui Wang1,
  • Steven D. Briscoe1,
  • Robert S. Rosenson  ORCID: orcid.org/0000-0002-5599-06332,
  • Christopher J. Cheng  ORCID: orcid.org/0009-0008-8092-51991,
  • Ellen Rohde1,
  • Joseph Biedenkapp1,
  • Victor Farutin1,
  • Andrew M. Bellinger1,3,
  • Kiran Musunuru  ORCID: orcid.org/0000-0003-3298-03684,5,6,
  • Sekar Kathiresan1,
  • Troy Lister1,
  • Kallanthottathil G. Rajeev1,
  • Richard G. Lee1 &
  • …
  • Amit V. Khera  ORCID: orcid.org/0000-0001-6535-58391 

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Abstract

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.

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Authors and Affiliations

  1. 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

  2. Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert S. Rosenson

  3. GV Management Company, LLC, Boston, MA, USA

    Andrew M. Bellinger

  4. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Kiran Musunuru

  5. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Kiran Musunuru

  6. Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Kiran Musunuru

Authors

  1. Taiji Mizoguchi
  2. Jamie E. DeNizio
  3. Alexandra C. Chadwick
  4. Anne Marie Mazzola
  5. Maxwell P. Brown
  6. Shashank Mishra
  7. Manashree Damle
  8. Yuri Matsumoto
  9. Victoria Neang
  10. Ryan Garrity
  11. Manini Mantri
  12. Joy Oshoname Olorife
  13. Hui-Ting Hsu
  14. Vian Peshdary
  15. Estela Shabani
  16. John D. Ganey
  17. Ryan Santos
  18. Anthony Federico
  19. Sara P. Garcia
  20. Pengying Hao
  21. Yue Wu
  22. Zachary Glass
  23. Lisa N. Kasiewicz
  24. Caroline Summers
  25. Athul Sanjeev
  26. Kui Wang
  27. Steven D. Briscoe
  28. Robert S. Rosenson
  29. Christopher J. Cheng
  30. Ellen Rohde
  31. Joseph Biedenkapp
  32. Victor Farutin
  33. Andrew M. Bellinger
  34. Kiran Musunuru
  35. Sekar Kathiresan
  36. Troy Lister
  37. Kallanthottathil G. Rajeev
  38. Richard G. Lee
  39. Amit V. Khera

Corresponding author

Correspondence to Amit V. Khera.

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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

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  • DOI: https://doi.org/10.1038/s41586-026-11233-9