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. In...

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Published in:	Science (American Association for the Advancement of Science) Vol. 384; no. 6701; pp. 1196 - 1202
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 14-06-2024
Subjects:	Animals CRISPR-Cas Systems Cystic fibrosis Cystic Fibrosis - genetics Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator - genetics Editing Epithelial Cells - metabolism Gene Editing Genetic disorders Genetic modification Genetic Therapy - methods Humans Lipids Liposomes Lung - metabolism Lungs Mice Nanoparticles Organoids Reagents Stem cells Stem Cells - metabolism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0036-8075 1095-9203 1095-9203
DOI:	10.1126/science.adk9428