In vivo editing of lung stem cells for durable gene correction in mice

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial…

• CP
  Cancer Prevention and Research Institute of Texas

  Award: RP210099
• UO
  University of Texas Southwestern Medical Center

  Award: P30CA142543
• CW
  Case Western Reserve University
• NI
  National Institutes of Health

  Awards: P30CA142543, SCR_017949, R01 EB025192-01A1, EB025192
• NC
  National Cancer Institute
• NI
  National Institute of Biomedical Imaging and Bioengineering

  Awards: EB025192-01A1, R01 EB025192-01A1