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In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates

Author

Listed:
  • Kiran Musunuru

    (Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania)

  • Alexandra C. Chadwick

    (Verve Therapeutics)

  • Taiji Mizoguchi

    (Verve Therapeutics)

  • Sara P. Garcia

    (Verve Therapeutics)

  • Jamie E. DeNizio

    (Verve Therapeutics)

  • Caroline W. Reiss

    (Verve Therapeutics)

  • Kui Wang

    (Verve Therapeutics)

  • Sowmya Iyer

    (Verve Therapeutics)

  • Chaitali Dutta

    (Verve Therapeutics)

  • Victoria Clendaniel

    (Verve Therapeutics)

  • Michael Amaonye

    (Verve Therapeutics)

  • Aaron Beach

    (Verve Therapeutics)

  • Kathleen Berth

    (Verve Therapeutics)

  • Souvik Biswas

    (Verve Therapeutics)

  • Maurine C. Braun

    (Verve Therapeutics)

  • Huei-Mei Chen

    (Verve Therapeutics)

  • Thomas V. Colace

    (Verve Therapeutics)

  • John D. Ganey

    (Verve Therapeutics)

  • Soumyashree A. Gangopadhyay

    (Verve Therapeutics)

  • Ryan Garrity

    (Verve Therapeutics)

  • Lisa N. Kasiewicz

    (Verve Therapeutics)

  • Jennifer Lavoie

    (Verve Therapeutics)

  • James A. Madsen

    (Verve Therapeutics)

  • Yuri Matsumoto

    (Verve Therapeutics)

  • Anne Marie Mazzola

    (Verve Therapeutics)

  • Yusuf S. Nasrullah

    (Verve Therapeutics)

  • Joseph Nneji

    (Verve Therapeutics)

  • Huilan Ren

    (Verve Therapeutics)

  • Athul Sanjeev

    (Verve Therapeutics)

  • Madeleine Shay

    (Verve Therapeutics)

  • Mary R. Stahley

    (Verve Therapeutics)

  • Steven H. Y. Fan

    (Acuitas Therapeutics)

  • Ying K. Tam

    (Acuitas Therapeutics)

  • Nicole M. Gaudelli

    (Beam Therapeutics)

  • Giuseppe Ciaramella

    (Beam Therapeutics)

  • Leslie E. Stolz

    (Verve Therapeutics)

  • Padma Malyala

    (Verve Therapeutics)

  • Christopher J. Cheng

    (Verve Therapeutics)

  • Kallanthottathil G. Rajeev

    (Verve Therapeutics)

  • Ellen Rohde

    (Verve Therapeutics)

  • Andrew M. Bellinger

    (Verve Therapeutics)

  • Sekar Kathiresan

    (Verve Therapeutics)

Abstract

Gene-editing technologies, which include the CRISPR–Cas nucleases1–3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.

Suggested Citation

  • Kiran Musunuru & Alexandra C. Chadwick & Taiji Mizoguchi & Sara P. Garcia & Jamie E. DeNizio & Caroline W. Reiss & Kui Wang & Sowmya Iyer & Chaitali Dutta & Victoria Clendaniel & Michael Amaonye & Aar, 2021. "In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates," Nature, Nature, vol. 593(7859), pages 429-434, May.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7859:d:10.1038_s41586-021-03534-y
    DOI: 10.1038/s41586-021-03534-y
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    Citations

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    Cited by:

    1. Yue Xu & Shihao Ma & Haotian Cui & Jingan Chen & Shufen Xu & Fanglin Gong & Alex Golubovic & Muye Zhou & Kevin Chang Wang & Andrew Varley & Rick Xing Ze Lu & Bo Wang & Bowen Li, 2024. "AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Lisa N. Kasiewicz & Souvik Biswas & Aaron Beach & Huilan Ren & Chaitali Dutta & Anne Marie Mazzola & Ellen Rohde & Alexandra Chadwick & Christopher Cheng & Sara P. Garcia & Sowmya Iyer & Yuri Matsumot, 2023. "GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Elliot H. Choi & Susie Suh & Andrzej T. Foik & Henri Leinonen & Gregory A. Newby & Xin D. Gao & Samagya Banskota & Thanh Hoang & Samuel W. Du & Zhiqian Dong & Aditya Raguram & Sajeev Kohli & Seth Blac, 2022. "In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Hongzhi Zeng & Qichen Yuan & Fei Peng & Dacheng Ma & Ananya Lingineni & Kelly Chee & Peretz Gilberd & Emmanuel C. Osikpa & Zheng Sun & Xue Gao, 2023. "A split and inducible adenine base editor for precise in vivo base editing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Dominique L. Brooks & Manuel J. Carrasco & Ping Qu & William H. Peranteau & Rebecca C. Ahrens-Nicklas & Kiran Musunuru & Mohamad-Gabriel Alameh & Xiao Wang, 2023. "Rapid and definitive treatment of phenylketonuria in variant-humanized mice with corrective editing," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    6. Zhenxing Yu & Zhike Lu & Jingjing Li & Yingying Wang & Panfeng Wu & Yini Li & Yangfan Zhou & Bailun Li & Heng Zhang & Yingzheng Liu & Lijia Ma, 2022. "PEAC-seq adopts Prime Editor to detect CRISPR off-target and DNA translocation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Qinchang Chen & Guohui Chuai & Haihang Zhang & Jin Tang & Liwen Duan & Huan Guan & Wenhui Li & Wannian Li & Jiaying Wen & Erwei Zuo & Qing Zhang & Qi Liu, 2023. "Genome-wide CRISPR off-target prediction and optimization using RNA-DNA interaction fingerprints," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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