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

Yehui Sun; Sumanta Chatterjee; Xizhen Lian; Zachary Traylor; Sandhya R. Sattiraju; Yufen Xiao; Sean A. Dilliard; Yun Chieh Sung; Minjeong Kim; Sang M. Lee; Stephen Moore; Xu Wang; Di Zhang; Shiying Wu; Pratima Basak; Jialu Wang; Jing Liu; Rachel J. Mann; David F. LePage; Weihong Jiang; Shadaan Abid; Mirko Hennig; Anna Martinez; Brandon A. Wustman; David J. Lockhart; Raksha Jain; Ronald A. Conlon; Mitchell L. Drumm; Craig A. Hodges; Daniel J. Siegwart

doi:10.1126/science.adk9428

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

Yehui Sun, Sumanta Chatterjee, Xizhen Lian, Zachary Traylor, Sandhya R. Sattiraju, Yufen Xiao, Sean A. Dilliard, Yun Chieh Sung, Minjeong Kim, Sang M. Lee, Stephen Moore, Xu Wang, Di Zhang, Shiying Wu, Pratima Basak, Jialu Wang, Jing Liu, Rachel J. Mann, David F. LePage, Weihong JiangShadaan Abid, Mirko Hennig, Anna Martinez, Brandon A. Wustman, David J. Lockhart, Raksha Jain, Ronald A. Conlon, Mitchell L. Drumm, Craig A. Hodges, Daniel J. Siegwart

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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.

Original language	English (US)
Pages (from-to)	1196-1202
Number of pages	7
Journal	Science (New York, N.Y.)
Volume	384
Issue number	6701
DOIs	https://doi.org/10.1126/science.adk9428
State	Published - Jun 14 2024
Externally published	Yes

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Sun, Y., Chatterjee, S., Lian, X., Traylor, Z., Sattiraju, S. R., Xiao, Y., Dilliard, S. A., Sung, Y. C., Kim, M., Lee, S. M., Moore, S., Wang, X., Zhang, D., Wu, S., Basak, P., Wang, J., Liu, J., Mann, R. J., LePage, D. F., ... Siegwart, D. J. (2024). In vivo editing of lung stem cells for durable gene correction in mice. Science (New York, N.Y.), 384(6701), 1196-1202. https://doi.org/10.1126/science.adk9428

Sun, Y, Chatterjee, S, Lian, X, Traylor, Z, Sattiraju, SR, Xiao, Y, Dilliard, SA, Sung, YC, Kim, M, Lee, SM, Moore, S, Wang, X, Zhang, D, Wu, S, Basak, P, Wang, J, Liu, J, Mann, RJ, LePage, DF, Jiang, W, Abid, S, Hennig, M, Martinez, A, Wustman, BA, Lockhart, DJ, Jain, R, Conlon, RA, Drumm, ML, Hodges, CA & Siegwart, DJ 2024, 'In vivo editing of lung stem cells for durable gene correction in mice', Science (New York, N.Y.), vol. 384, no. 6701, pp. 1196-1202. https://doi.org/10.1126/science.adk9428

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title = "In vivo editing of lung stem cells for durable gene correction in mice",

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.",

author = "Yehui Sun and Sumanta Chatterjee and Xizhen Lian and Zachary Traylor and Sattiraju, {Sandhya R.} and Yufen Xiao and Dilliard, {Sean A.} and Sung, {Yun Chieh} and Minjeong Kim and Lee, {Sang M.} and Stephen Moore and Xu Wang and Di Zhang and Shiying Wu and Pratima Basak and Jialu Wang and Jing Liu and Mann, {Rachel J.} and LePage, {David F.} and Weihong Jiang and Shadaan Abid and Mirko Hennig and Anna Martinez and Wustman, {Brandon A.} and Lockhart, {David J.} and Raksha Jain and Conlon, {Ronald A.} and Drumm, {Mitchell L.} and Hodges, {Craig A.} and Siegwart, {Daniel J.}",

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doi = "10.1126/science.adk9428",

language = "English (US)",

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AU - Sun, Yehui

AU - Chatterjee, Sumanta

AU - Lian, Xizhen

AU - Traylor, Zachary

AU - Sattiraju, Sandhya R.

AU - Xiao, Yufen

AU - Dilliard, Sean A.

AU - Sung, Yun Chieh

AU - Kim, Minjeong

AU - Lee, Sang M.

AU - Moore, Stephen

AU - Wang, Xu

AU - Zhang, Di

AU - Wu, Shiying

AU - Basak, Pratima

AU - Wang, Jialu

AU - Liu, Jing

AU - Mann, Rachel J.

AU - LePage, David F.

AU - Jiang, Weihong

AU - Abid, Shadaan

AU - Hennig, Mirko

AU - Martinez, Anna

AU - Wustman, Brandon A.

AU - Lockhart, David J.

AU - Jain, Raksha

AU - Conlon, Ronald A.

AU - Drumm, Mitchell L.

AU - Hodges, Craig A.

AU - Siegwart, Daniel J.

PY - 2024/6/14

Y1 - 2024/6/14

N2 - 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.

AB - 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.

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

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