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Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients
Open accessAbstract
Single murine and human intestinal stem cells can be expanded in culture over long time periods as genetically and phenotypically stable epithelial organoids. Increased cAMP levels induce rapid swelling of such organoids by opening the cystic fibrosis transmembrane conductor receptor (CFTR). This response is lost in organoids derived from cystic fibrosis (CF) patients. Here we use the CRISPR/Cas9 genome editing system to correct the CFTR locus by homologous recombination in cultured intestinal stem cells of CF patients. The corrected allele is expressed and fully functional as measured in clonally expanded organoids. This study provides proof of concept for gene correction by homologous recombination in primary adult stem cells derived from patients with a single-gene hereditary defect.
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“The CRISPR-nuclease SpCas9 was harnessed to correct the ΔF508 mutation by homology-directed repair (HDR)22.”
From Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing (2019) · cites this paper as [22]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“providing the first step to advance gene therapy in cystic fibrosis patients with CRISPR.”
From CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool (2019) · cites this paper as [167]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“They demonstrated that once the mutation had been corrected, the function of the CF transmembrane conductor receptor (CFTR) was restored.4”
From What is CRISPR/Cas9? (2016) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Using adult intestinal stem cells obtained from two patients with CF, they successfully corrected the most common mutation causing CF in intestinal organoids.”
From What is CRISPR/Cas9? (2016) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Using CRISPR, researchers were able to correct mutant intestinal stem cells from cystic fibrosis patients and restore their function in vitro [167]”
From CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool (2019) · cites this paper as [167]
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“In 2013, researchers culture intestinal stem cells from two cystic fibrosis patients and corrected the mutation at the CFTR locus resulting in the expression of the correct gene and full function of the protein.”
From Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing (2021) · cites this paper as [33]
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“Since then, the potential utility of the application of CRISPR/Cas-9 for cystic fibrosis was established.33”
From Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing (2021) · cites this paper as [33]
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In the citing paper
“For instance, organoids derived from intestinal epithelial cells of pediatric IBD patients had IBD-specific DNA methylation signatures despite retaining similar morphologies195.”
From Organoids (2022) · cites this paper as [195]
Experimental — accuracy not yet measuredIn the citing paper
“Several groups have also demonstrated in vitro correction of genetic disease genes including CFTR (cystic fibrosis)9, Crygc (cataracts)10 and DMD (Duchenne muscular dystrophy)11 in organoids or mouse zygotes.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [9]
In the citing paper
“correct the cystic fibrosis transmembrane conductor receptor locus in cultured intestinal stem cells of cystic fibrosis patients (Schwank et al., 2013)”
From Delivering CRISPR: a review of the challenges and approaches (2018) · cites this paper as Schwank et al., 2013
In the citing paper
“CRISPR-Cas9 genome editing has been applied to correct disease-causing mutations in mouse zygotes and human cell lines for cataract5 and cystic fibrosis6”
From Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype (2014) · cites this paper as [6]
In the citing paper
“In human intestinal stem cells collected from patients with cystic fibrosis, the culprit gene cystic fibrosis transmembrane conductance regulator was rectified by homologous recombination during CRISPR-Cas9 genome editing while the pluripotency was retained as demonstrated by formations of organ-like expansions in cell culture.33”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [33]
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“The Clevers lab pioneered the application of CRISPR/Cas9 technology to organoid cultures and used it to correct mutations and restore the chloride channel function of CF-patient-derived intestinal organoids (Schwank et al., 2013).”
Saxena, K., Blutt, S. E., Ettayebi, K., Zeng, X.-L., Broughman, J. R., Crawford, S. E., Karandikar, U. C., Sastri, N. P., Conner, M. E., Opekun, A. R., et al. (2016) · Journal of Virology · doi:10.1128/jvi.01930-15 · Cited by 375
Efficient genetic engineering of human intestinal organoids using electroporation
Fujii, M., Matano, M., Nanki, K., & Sato, T. (2015) · Nature Protocols · doi:10.1038/nprot.2015.088 · Cited by 364
Target specificity of the CRISPR‐Cas9 system
Wu, X., Kriz, A. J., & Sharp, P. A. (2014) · Quantitative Biology · doi:10.1007/s40484-014-0030-x · Cited by 388
“With exogenous template oligos, specific sequences such as HA-tag or GFP could be inserted into genes to label proteins [19,20], or to correct mutations in disease genes in human and mouse [21–23].”
Organoids — Preclinical Models of Human Disease
Li, M., & Belmonte, J. C. I. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1806175 · Cited by 373
Single luminal epithelial progenitors can generate prostate organoids in culture
Chua, C. W., Shibata, M., Lei, M., Toivanen, R., Barlow, L. J., Bergren, S. K., Badani, K. K., McKiernan, J. M., Benson, M. C., Hibshoosh, H. H., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3047 · Cited by 361
Tak, Y. G., & Farnham, P. (2015) · Epigenetics & Chromatin · doi:10.1186/s13072-015-0050-4 · Cited by 353
“Investigators have begun to use 3 dimensional organoids [123], normal cell lines, or isogenic ES or iPS cells [124, 125] to try to reproduce a more natural cellular environment for functional studies.”
BackgroundIn vivo genome editing and organoid transplantation models of colorectal cancer and metastasis
Roper, J., Tammela, T., Cetinbas, N. M., Akkad, A., Roghanian, A., Rickelt, S., Almeqdadi, M., Wu, K., Oberli, M. A., Rivera, F. J. S., et al. (2017) · Nature Biotechnology · doi:10.1038/nbt.3836 · Cited by 356
Canver, M. C., Bauer, D. E., Dass, A., Yien, Y. Y., Chung, J., Masuda, T., Maeda, T., Paw, B. H., & Orkin, S. H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.564625 · Cited by 357
“cally inactive Cas9 (14), pooled sgRNA library screening for functional genomics (15–17), and potential CRISPR-based therapy highlighted by its recent use for gene correction in both murine and human stem cells (18, 19).”
BackgroundSmith, C., Gore, A., Yan, W., Abalde-Atristain, L., Li, Z., He, C., Wang, Y., Brodsky, R. A., Zhang, K., Cheng, L., et al. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.06.011 · Cited by 342
“Some recent studies, including one on human adult stem cells, showed a minimal level of off-target effects by CRISPR/Cas9 (Schwank et al., 2013).”
BackgroundHuman tissues in a dish: The research and ethical implications of organoid technology
Bredenoord, A. L., Clevers, H., & Knoblich, J. A. (2017) · Science · doi:10.1126/science.aaf9414 · Cited by 334
“Indeed, the CFTR gene mutation has been corrected using CRISPR-Cas9 in organoids derived from two cystic fibrosis patients (56).”
Self-citationDivergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis
Nanki, K., Toshimitsu, K., Takano, A., Fujii, M., Shimokawa, M., Ohta, Y., Matano, M., Seino, T., Nishikori, S., Ishikawa, K., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.027 · Cited by 341
Self-citationHeichler, C., Koop, K., Schmied, A., Geppert, C. I., Schmid, B., Wirtz, S. J., Thoma, O., Kramer, V., Waldner, M. J., Büttner, C., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-319200 · Cited by 330
CRISPR/Cas9 for cancer research and therapy
Zhan, T., Rindtorff, N., Betge, J., Ebert, M., & Boutros, M. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.04.001 · Cited by 338
Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs
Firth, A. L., Menon, T., Parker, G. S., Qualls, S. J., Lewis, B. M., Ke, E., Dargitz, C., Wright, R., Khanna, A., Gage, F. H., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.062 · Cited by 337
Ong, T., & Ramsey, B. W. (2023) · JAMA · doi:10.1001/jama.2023.8120 · Cited by 346
CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool
Brokowski, C., & Adli, M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.05.044 · Cited by 320
Current Biomedical Applications of 3D Printing and Additive Manufacturing
Ahangar, P., Cooke, M. E., Weber, M. H., & Rosenzweig, D. H. (2019) · Applied Sciences · doi:10.3390/app9081713 · Cited by 329
Artegiani, B., Hendriks, D. F. G., Beumer, J., Kok, R. N. U., Zheng, X., Joore, I. P., Lopes, S. M. C. D. S., van Zon, J. S., Tans, S. J., & Clevers, H. C. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0472-5 · Cited by 313
Self-citationPost-translational Regulation of Cas9 during G1 Enhances Homology-Directed Repair
Gutschner, T., Hämmerle, M., Genovese, G., Draetta, G. F., & Chin, L. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.019 · Cited by 306
Zachos, N. C., Kovbasnjuk, O. N., Foulke-Abel, J. D., In, J., Blutt, S. E., de Jonge, H. R., Estes, M. K., & Donowitz, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.635995 · Cited by 308
“In addition, methods have been established to alter gene expression either by overexpression or shRNA-mediated knockdown using lipophilic transfection reagents and virusmediated transduction (14, 57).”
MethodRecent Advances in CRISPR/Cas9 Delivery Strategies
Yip, B. (2020) · Biomolecules · doi:10.3390/biom10060839 · Cited by 292
CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases
Sharma, G., Sharma, A. R., Bhattacharya, M., Lee, S., & Chakraborty, C. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.09.028 · Cited by 310
“In primary adult stem cells, CFTR gene alteration was done through homologous recombination.(57) Therefore, CRISPR technology might be a potential approach for the treatment of CF in future.”
BackgroundMethodGrowth of Epithelial Organoids in a Defined Hydrogel
Broguiere, N., Isenmann, L., Hirt, C., Ringel, T., Placzek, S., Cavalli, E., Ringnalda, F., Villiger, L., Züllig, R., Lehmann, R., et al. (2018) · Advanced Materials · doi:10.1002/adma.201801621 · Cited by 282
Self-citationTALEN and CRISPR/Cas Genome Editing Systems: Tools of Discovery
Nemudryi, A. A., Valetdinova, K. R., Medvedev, S. P., & Zakian, S. M. (2014) · Acta Naturae · doi:10.32607/20758251-2014-6-3-19-40 · Cited by 287
Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach
Leushacke, M., Tan, S. H., Wong, A. M. L., Yada, S., Hajamohideen, A., Tan, L. T., Goh, J., Wong, E. S. P., Denil, S. L. I. J., Murakami, K., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3541 · Cited by 281
Personalized Cancer Medicine: An Organoid Approach
Es, H. A., Montazeri, L., Aref, A. R., Vosough, M., & Baharvand, H. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2017.12.005 · Cited by 286
Machine Learning in Genomic Medicine: A Review of Computational Problems and Data Sets
Leung, M. K. K., Delong, A., Alipanahi, B., & Frey, B. J. (2015) · Proceedings of the IEEE · doi:10.1109/jproc.2015.2494198 · Cited by 284
“The system has been used to control gene expression by deactivating the endonuclease domain [201], study gene functions in neural cells [202], develop synthetic biology applications [203], fix pathogenic mutations causing -thalassemia [204], and to repair cystic fibrosis transmembrane conductor receptor mutations [205…”
MethodOrganoids: The current status and biomedical applications
Yang, S., Hu, H., Kung, H., Zou, R.-Q., Dai, Y.-S., Hu, Y.-F., Wang, T., Lv, T., Yu, J., & Li, F. (2023) · MedComm · doi:10.1002/mco2.274 · Cited by 300
Genome modification by CRISPR /Cas9
Ma, Y., Zhang, L., & Huang, X. (2014) · FEBS Journal · doi:10.1111/febs.13110 · Cited by 304
CRISPR/Cas9‐mediated genome engineering: An adeno‐associated viral (AAV) vector toolbox
Senís, E., Fatouros, C., Große, S., Wiedtke, E., Niopek, D., Mueller, A., Börner, K., & Grimm, D. (2014) · Biotechnology Journal · doi:10.1002/biot.201400046 · Cited by 268
Fumagalli, A., Drost, J., Suijkerbuijk, S. J. E., van Boxtel, R., de Ligt, J., Offerhaus, G. J. A., Begthel, H., Beerling, E., Tan, E. H., Sansom, O. J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701219114 · Cited by 268
“The GFP targeting sequencewas exchanged by inverse PCR followed byDpnI digestion and T4 ligation as described (7, 24).”
MethodSelf-citationEstablishment and Culture of Human Intestinal Organoids Derived from Adult Stem Cells
Pleguezuelos‐Manzano, C., Puschhof, J., van den Brink, S., Geurts, V., Beumer, J., & Clevers, H. C. (2020) · Current Protocols in Immunology · doi:10.1002/cpim.106 · Cited by 277
“By repairing these mutations using CRISPR/Cas9-based genetic engineering in the patient-derived organoids, this technology might be used in future regenerative medicine approaches (Geurts et al., 2020; Schwank et al., 2013).”
MethodSelf-citationCFTR: cystic fibrosis and beyond
Mall, M. A., & Hartl, D. (2014) · European Respiratory Journal · doi:10.1183/09031936.00228013 · Cited by 266
Advances in therapeutic CRISPR/Cas9 genome editing
Savić, N., & Schwank, G. (2016) · Translational Research · doi:10.1016/j.trsl.2015.09.008 · Cited by 257
Self-citationCheroni, C., Caporale, N., & Testa, G. (2020) · Molecular Autism · doi:10.1186/s13229-020-00370-1 · Cited by 290
Cystic fibrosis: current therapeutic targets and future approaches
Rafeeq, M. M., & Murad, H. A. S. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-017-1193-9 · Cited by 287
“There is one proof of concept study in intestinal stem cell organoids of CF patients carrying two F508del mutations with CRISPR/Cas9 methodology [68].”
BackgroundMarinko, J. T., Huang, H., Penn, W. D., Capra, J. A., Schlebach, J. P., & Sanders, C. R. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00532 · Cited by 257
Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium
Miyoshi, H., VanDussen, K. L., Malvin, N. P., Ryu, H., Wang, Y., Sonnek, N. M., Lai, C., & Stappenbeck, T. S. (2016) · The EMBO Journal · doi:10.15252/embj.201694660 · Cited by 252
“The morphologic effects were similar to previous reports using forskolin (Dekkers et et al , 2013). cAMP is known to activate a multitude of effector proteins.”
Metadata
- Authors
- Schwank, G., Koo, B.-K., Sasselli, V., Dekkers, J. F., Heo, I., Demircan, T., Sasaki, N., Boymans, S., Cuppen, E., van der Ent, C. K., Nieuwenhuis, E. E. S., Beekman, J. M., & Clevers, H.
- Affiliations
- University Medical Center Utrecht (NL)
- Wilhelmina Children's Hospital (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- Corresponding author
- Clevers, Hans
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 13
- Issue
- 6
- Pages
- 653-658
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W1986316308
- Cited by
- 1,424
- References
- 45
- Citations by year
- 2026: 64 · 2025: 74 · 2024: 92 · 2023: 78 · 2022: 105 · 2021: 152 · 2020: 137 · 2019: 120 · 2018: 118 · 2017: 148 · 2016: 150 · 2015: 110 · 2014: 72 · 2013: 3
- FWCI
- 50.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Wellcome Trust (079249, 097922/C/11/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- cystic fibrosis, CFTR, CRISPR/Cas9 genome editing, homologous recombination, gene correction, cAMP signaling, adult stem cells
- MeSH terms
- Adult, Animals, Base Sequence, Cystic Fibrosis, Humans, Intestines, Molecular Sequence Data, Organoids, Stem Cells, Genetic Therapy, RNA Editing, Cystic Fibrosis Transmembrane Conductance Regulator, Mice, Adult Stem Cells, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Associated Proteins
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