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

Science. 2024 Jun 14;384(6701):1196-1202. doi: 10.1126/science.adk9428. Epub 2024 Jun 13.

Abstract

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 epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis* / genetics
  • Cystic Fibrosis* / therapy
  • Epithelial Cells / metabolism
  • Gene Editing*
  • Genetic Therapy / methods
  • Humans
  • Liposomes*
  • Lung* / metabolism
  • Mice
  • Nanoparticles*
  • Organoids
  • Stem Cells* / metabolism

Substances

  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Lipid Nanoparticles
  • Liposomes