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Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models

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Listed:
  • Tuo Wei

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Yehui Sun

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Qiang Cheng

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Sumanta Chatterjee

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Zachary Traylor

    (Case Western Reserve University School of Medicine
    Case Western Reserve University School of Medicine)

  • Lindsay T. Johnson

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Melissa L. Coquelin

    (ReCode Therapeutics)

  • Jialu Wang

    (ReCode Therapeutics)

  • Michael J. Torres

    (ReCode Therapeutics)

  • Xizhen Lian

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Xu Wang

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Yufen Xiao

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Craig A. Hodges

    (Case Western Reserve University School of Medicine
    Case Western Reserve University School of Medicine)

  • Daniel J. Siegwart

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

Abstract

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

Suggested Citation

  • Tuo Wei & Yehui Sun & Qiang Cheng & Sumanta Chatterjee & Zachary Traylor & Lindsay T. Johnson & Melissa L. Coquelin & Jialu Wang & Michael J. Torres & Xizhen Lian & Xu Wang & Yufen Xiao & Craig A. Hod, 2023. "Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42948-2
    DOI: 10.1038/s41467-023-42948-2
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    References listed on IDEAS

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    1. Tuo Wei & Qiang Cheng & Yi-Li Min & Eric N. Olson & Daniel J. Siegwart, 2020. "Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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    Cited by:

    1. Kexin Su & Lu Shi & Tao Sheng & Xinxin Yan & Lixin Lin & Chaoyang Meng & Shiqi Wu & Yuxuan Chen & Yao Zhang & Chaorong Wang & Zichuan Wang & Junjie Qiu & Jiahui Zhao & Tengfei Xu & Yuan Ping & Zhen Gu, 2024. "Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Shuai Liu & Yixing Wen & Xinzhu Shan & Xinghuan Ma & Chen Yang & Xingdi Cheng & Yuanyuan Zhao & Jingjiao Li & Shiwei Mi & Haonan Huo & Wei Li & Ziqiong Jiang & Yijia Li & Jiaqi Lin & Lei Miao & Xuegua, 2024. "Charge-assisted stabilization of lipid nanoparticles enables inhaled mRNA delivery for mucosal vaccination," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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