Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene
Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespa...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-01-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.139813 |
| _version_ | 1818614104069242880 |
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| author | Jie Xu Alessandra Livraghi-Butrico Xia Hou Carthic Rajagopalan Jifeng Zhang Jun Song Hong Jiang Hong-Guang Wei Hui Wang Mohamad Bouhamdan Jinxue Ruan Dongshan Yang Yining Qiu Youming Xie Ronald Barrett Sharon McClellan Hongmei Mou Qingtian Wu Xuequn Chen Troy D. Rogers Kristen J. Wilkinson Rodney C. Gilmore Charles R. Esther Jr. Khalequz Zaman Xiubin Liang Michael Sobolic Linda Hazlett Kezhong Zhang Raymond A. Frizzell Martina Gentzsch Wanda K. O’Neal Barbara R. Grubb Y. Eugene Chen Richard C. Boucher Fei Sun |
| author_facet | Jie Xu Alessandra Livraghi-Butrico Xia Hou Carthic Rajagopalan Jifeng Zhang Jun Song Hong Jiang Hong-Guang Wei Hui Wang Mohamad Bouhamdan Jinxue Ruan Dongshan Yang Yining Qiu Youming Xie Ronald Barrett Sharon McClellan Hongmei Mou Qingtian Wu Xuequn Chen Troy D. Rogers Kristen J. Wilkinson Rodney C. Gilmore Charles R. Esther Jr. Khalequz Zaman Xiubin Liang Michael Sobolic Linda Hazlett Kezhong Zhang Raymond A. Frizzell Martina Gentzsch Wanda K. O’Neal Barbara R. Grubb Y. Eugene Chen Richard C. Boucher Fei Sun |
| author_sort | Jie Xu |
| collection | DOAJ |
| description | Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of approximately 40 days and died of gastrointestinal disease, but therapeutic regimens directed toward restoring gastrointestinal transit extended median survival to approximately 80 days. Surrogate markers of exocrine pancreas disorders were found in CF rabbits with declining health. CFTR expression patterns in WT rabbit airways mimicked humans, with widespread distribution in nasal respiratory and olfactory epithelia, as well as proximal and distal lower airways. CF rabbits exhibited human CF–like abnormalities in the bioelectric properties of the nasal and tracheal epithelia. No spontaneous respiratory disease was detected in young CF rabbits. However, abnormal phenotypes were observed in surviving 1-year-old CF rabbits as compared with WT littermates, and these were especially evident in the nasal respiratory and olfactory epithelium. The CF rabbit model may serve as a useful tool for understanding gut and lung CF pathogenesis and for the practical development of CF therapeutics. |
| first_indexed | 2024-12-16T16:12:42Z |
| format | Article |
| id | doaj.art-ff264f8cd5104415abd1eba07591062e |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-16T16:12:42Z |
| publishDate | 2021-01-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-ff264f8cd5104415abd1eba07591062e2022-12-21T22:25:11ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-01-0161Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR geneJie XuAlessandra Livraghi-ButricoXia HouCarthic RajagopalanJifeng ZhangJun SongHong JiangHong-Guang WeiHui WangMohamad BouhamdanJinxue RuanDongshan YangYining QiuYouming XieRonald BarrettSharon McClellanHongmei MouQingtian WuXuequn ChenTroy D. RogersKristen J. WilkinsonRodney C. GilmoreCharles R. Esther Jr.Khalequz ZamanXiubin LiangMichael SobolicLinda HazlettKezhong ZhangRaymond A. FrizzellMartina GentzschWanda K. O’NealBarbara R. GrubbY. Eugene ChenRichard C. BoucherFei SunExisting animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of approximately 40 days and died of gastrointestinal disease, but therapeutic regimens directed toward restoring gastrointestinal transit extended median survival to approximately 80 days. Surrogate markers of exocrine pancreas disorders were found in CF rabbits with declining health. CFTR expression patterns in WT rabbit airways mimicked humans, with widespread distribution in nasal respiratory and olfactory epithelia, as well as proximal and distal lower airways. CF rabbits exhibited human CF–like abnormalities in the bioelectric properties of the nasal and tracheal epithelia. No spontaneous respiratory disease was detected in young CF rabbits. However, abnormal phenotypes were observed in surviving 1-year-old CF rabbits as compared with WT littermates, and these were especially evident in the nasal respiratory and olfactory epithelium. The CF rabbit model may serve as a useful tool for understanding gut and lung CF pathogenesis and for the practical development of CF therapeutics.https://doi.org/10.1172/jci.insight.139813Cell biologyPulmonology |
| spellingShingle | Jie Xu Alessandra Livraghi-Butrico Xia Hou Carthic Rajagopalan Jifeng Zhang Jun Song Hong Jiang Hong-Guang Wei Hui Wang Mohamad Bouhamdan Jinxue Ruan Dongshan Yang Yining Qiu Youming Xie Ronald Barrett Sharon McClellan Hongmei Mou Qingtian Wu Xuequn Chen Troy D. Rogers Kristen J. Wilkinson Rodney C. Gilmore Charles R. Esther Jr. Khalequz Zaman Xiubin Liang Michael Sobolic Linda Hazlett Kezhong Zhang Raymond A. Frizzell Martina Gentzsch Wanda K. O’Neal Barbara R. Grubb Y. Eugene Chen Richard C. Boucher Fei Sun Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene JCI Insight Cell biology Pulmonology |
| title | Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene |
| title_full | Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene |
| title_fullStr | Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene |
| title_full_unstemmed | Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene |
| title_short | Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene |
| title_sort | phenotypes of cf rabbits generated by crispr cas9 mediated disruption of the cftr gene |
| topic | Cell biology Pulmonology |
| url | https://doi.org/10.1172/jci.insight.139813 |
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