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

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. Hodges and Daniel J. Siegwart ()
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Tuo Wei: The University of Texas Southwestern Medical Center
Yehui Sun: The University of Texas Southwestern Medical Center
Qiang Cheng: The University of Texas Southwestern Medical Center
Sumanta Chatterjee: The University of Texas Southwestern Medical Center
Zachary Traylor: Case Western Reserve University School of Medicine
Lindsay T. Johnson: 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
Xu Wang: The University of Texas Southwestern Medical Center
Yufen Xiao: The University of Texas Southwestern Medical Center
Craig A. Hodges: Case Western Reserve University School of Medicine
Daniel J. Siegwart: The University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42948-2

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