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

• 成果类型: Article
• 署名作者: Sun, Yehui; Chatterjee, Sumanta; Lian, Xizhen; Traylor, Zachary; Sattiraju, Sandhya R.; Xiao, Yufen; Dilliard, Sean A.; Sung, Yun-Chieh; Kim, Minjeong; Lee, Sang M.; Moore, Stephen; Wang, Xu; Zhang, Di; Wu, Shiying; Basak, Pratima; Wang, Jialu; Liu, Jing; Mann, Rachel J.; Lepage, David F.; Jiang, Weihong; Abid, Shadaan; Hennig, Mirko; Martinez, Anna; Wustman, Brandon A.; Lockhart, David J.; Jain, Raksha; Conlon, Ronald A.; Drumm, Mitchell L.; Hodges, Craig A.; Siegwart, Daniel J.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University System of Ohio; Case Western Reserve University; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11821
• DOI: 10.1126/science.adk9428
• 发表日期: 2024-06-14
• 页码: 1196-1202
• 关键词: cystic-fibrosis; basal-cells; delivery; vitro; cftr; regeneration; mechanisms; defect; dna

摘要

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.