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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.
In the citing paper
“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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“Several groups have also demonstrated correction of genetic disease genes, such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene in intestinal organoids [54], a dominant mutation in the Crygc gene that causes cataracts [55], and the Duchenne muscular dystrophy (Dmd) gene in mouse zygotes [56].”
BackgroundSpell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders
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“However, further genetic manipulations to prove the causal alleles (see below) become more challenging due to the larger number of genes involved, smaller phenotypic effects and the potential for epistasis between different alleles.”
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“Consider, for example, the correction of a cystic fibrosis transmembrane conductor receptor and the restoration of function in intestinal organoids generated from the tissue of affected patients (Schwank et al., 2013).”
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Probing human brain evolution and development in organoids
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“By combining CRISPR genome-editing and organoid culture we can introduce virtually any genetic changes in iPSCs and query their phenotypic effects in a complex 3D context, as demonstrated for intestinal organoids for example [68].”
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“…by the use of viral transduction, bacterial artificial chromosome (BAC) transfection or the CRISPR/Cas9 gene editing system (Koo et al., 2013, 2012; Schwank et al., 2013a,b) provide tools with which to knockdown, overexpress or even repair genes to study their functions, in a polarized epithelial…”
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“Development of muscular dystrophy in mutant mice has been prevented by correcting the dystrophin gene in germ line with coinjection of sgRNA, Cas9 and donor template into mouse zygotes (Schwank et al., 2013).”
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Organoids of the female reproductive tract
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“In the context of CF, Schwank and colleagues used the CRISPR–Cas9 technology to correct the CFTR locus in human and mouse intestinal organoids.(119) Similarly, Lee and colleagues used zinc finger nucleases to correct the F508del mutation in an in vitro model.”
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“By following the same theme, technique has been applied for developing transgenic animal models few years ago (Niu et al., 2014). iPS cell disease model were engineered with definite mutations corrected or introduced with gene correction in animals (Schwank et al., 2013).”
MethodSzvicsek, Z., Oszvald, Á., Szabó, L., Sándor, G. O., Kelemen, A., Soós, A. Á., Pálóczi, K., Harsányi, L., Tölgyes, T., Dede, K., et al. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03052-1 · Cited by 97
Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis
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AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer
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“To generate APTK and APTK-myrAKT organoids, the following constructs were used: (1) plasmid encoding the sgRNA targeting the Apc gene (sgRNA-Apc-T1; Schwank et al., 2013), (2) human myrAKT cloned downstream of IRES and hygromycin in rtTA3-PGKHygro, (3) murine KrasG12D cDNA cloned downstream of IRES and puromycin resis…”
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“phenotypically stable epithelial organoids.(15) In skeletal muscles, satellite cells are acknowledged as bona fide adult MuSCs being responsible for postnatal growth and regeneration of the muscle fiber.”
BackgroundStem Cells in Repair of Gastrointestinal Epithelia
Andersson-Rolf, A., Zilbauer, M., Koo, B., & Clevers, H. C. (2017) · Physiology · doi:10.1152/physiol.00005.2017 · Cited by 93
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BackgroundSelf-citationIntestinal organoids for modelling intestinal development and disease
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Lin, S., Qu, L., Ettayebi, K., Crawford, S. E., Blutt, S. E., Robertson, M. J., Zeng, X., Tenge, V. R., Ayyar, B. V., Karandikar, U. C., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2010834117 · Cited by 87
“G. Schwank et al., Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.”
CRISPR/Cas9 Landscape: Current State and Future Perspectives
Tyumentsev, A. I., Tyumentsev, A. I., & Акимкин, В. Г. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216077 · Cited by 98
Development and application of human adult stem or progenitor cell organoids
Rookmaaker, M. B., Schutgens, F., Verhaar, M. C., & Clevers, H. C. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.118 · Cited by 91
Self-citationNovel Epigenetic Techniques Provided by the CRISPR/Cas9 System
Xie, N., Zhou, Y., Sun, Q., & Tang, B. (2018) · Stem Cells International · doi:10.1155/2018/7834175 · Cited by 90
Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing
Maule, G., Arosio, D., & Cereseto, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113903 · Cited by 102
“CRISPR-Cas9 was proven valid to correct ∆F508 in advanced cellular models, such as intestinal organoids derived from patients, where CFTR channel function could be restored [53].”
BackgroundZheng, F., Xiao, Y., Liu, H., Fan, Y., & Dao, M. (2021) · Advanced Biology · doi:10.1002/adbi.202000024 · Cited by 96
Human Intestinal Tissue with Adult Stem Cell Properties Derived from Pluripotent Stem Cells
Forster, R. E., Chiba, K., Schaeffer, L., Regalado, S. G., Lai, C. S., Gao, Q., Kiani, S., Farin, H. F., Clevers, H. C., Cost, G. J., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.05.001 · Cited by 88
Self-citationOrganoid-based Models to Study the Role of Host-microbiota Interactions in IBD
Poletti, M., Arnauts, K., Ferrante, M., & Korcsmáros, T. (2020) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjaa257 · Cited by 93
The potential of organoids in urological cancer research
Wang, S., Gao, D., & Chen, Y. (2017) · Nature Reviews Urology · doi:10.1038/nrurol.2017.65 · Cited by 87
Stem cell-based Lung-on-Chips: The best of both worlds?
Nawroth, J. C., Barrile, R., Conegliano, D., van Riet, S., Hiemstra, P. S., & Villenave, R. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.07.005 · Cited by 89
“Recently, CRISPR-Cas9 genome editing technology was used to restore normal functional CFTR intestinal stem cell organoids, demonstrating the powerful potential of these systems for testing human gene therapy [189] .”
MethodEfficient Gene Editing at Major CFTR Mutation Loci
Ruan, J., Hirai, H., Yang, D., Ma, L., Hou, X., Jiang, H., Wei, H., Rajagopalan, C., Mou, H., Wang, G., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.02.006 · Cited by 90
“Without any drug selection, Schwank et al.(11) reported an 0.”
InfluentialHuman colon organoids reveal distinct physiologic and oncogenic Wnt responses
Michels, B. E., Mosa, M. H., Grebbin, B. M., Yepes, D., Darvishi, T., Hausmann, J., Urlaub, H., Zeuzem, S., Kvasnicka, H. M., Oellerich, T., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20180823 · Cited by 92
Future regenerative medicine developments and their therapeutic applications
Altyar, A. E., El-Sayed, A., Abdeen, A., Piscopo, M., Mousa, S. A., Najda, A., & Abdel‐Daim, M. M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114131 · Cited by 98
Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing
Maule, G., Casini, A., Montagna, C., Ramalho, A. S., De Boeck, K., Debyser, Z., Carlon, M. S., Petris, G., & Cereseto, A. (2019) · Nature Communications · doi:10.1038/s41467-019-11454-9 · Cited by 86
Organoids: An intermediate modeling platform in precision oncology
Jin, M., Han, R.-R., Qiu, G., Ju, X.-C., Lou, G., & Jin, W. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.11.021 · Cited by 90
Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases
Blutt, S. E., Crawford, S. E., Ramani, S., Zou, W. Y., & Estes, M. K. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.12.001 · Cited by 86
“In addition, they can be genetically manipulated by using transfection, electroporation, and lentivirus transduction.(13,15,16) These new experimental tools are applicable for both basic and translational research.”
BackgroundShin, J. J., Schröder, M., Caiado, F., Wyman, S. K., Bray, N., Bordi, M., DeWitt, M. A., Vu, J. T., Kim, W., Hockemeyer, D. F., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108093 · Cited by 87
“Multiple types of primary cells potentially suffer from poor HDR that may be linked to quiescence (Bressan et al., 2017; Schwank et al., 2013; Urnov et al., 2010; Zhu et al., 2017).”
BackgroundAdvanced human developmental toxicity and teratogenicity assessment using human organoid models
Li, M., Gong, J., Gao, L., Zou, T., Kang, J., & Xu, H. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.113429 · Cited by 84
Switching roles: the functional plasticity of adult tissue stem cells
Wabik, A., & Jones, P. H. (2015) · The EMBO Journal · doi:10.15252/embj.201490386 · Cited by 84
“In combination with genome editing, ex vivo stem cell expansion may be particularly powerful for treating genetic diseases with tissue-restricted phenotypes, where engrafted SCs can compete with host SCs on at least even terms (Schwank et al , 2013).”
Organoids as Models for Neoplastic Transformation
Neal, J. T., & Kuo, C. J. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044249 · Cited by 85
Ou, Z., Niu, X., He, W., Chen, Y., Song, B., Xian, Y., Fan, D., Tang, D., & Sun, X. (2016) · Scientific Reports · doi:10.1038/srep32463 · Cited by 84
In vitro models of the human endometrium: evolution and application for women’s health+
Fitzgerald, H. C., Schust, D. J., & Spencer, T. E. (2020) · Biology of Reproduction · doi:10.1093/biolre/ioaa183 · Cited by 84
“CRISPR has been used in organoids, particularly those involving disease-causing mutation; for example, mutations in the gene coding for cystic fibrosis could be repaired in organoids derived from cystic fibrosis [92].”
BackgroundRNA Interference in the Age of CRISPR: Will CRISPR Interfere with RNAi?
Unniyampurath, U., Pilankatta, R., & Krishnan, M. N. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17030291 · Cited by 88
“Examples for this include therapeutic use of CRISPR/Cas9 mediated ex vivo gene edited cells to treat Duchenne muscular dystrophy and cystic fibrosis [73,74].”
BackgroundHu, Z. M., Shi, Z., Guo, X., Jiang, B., Wang, G., Luo, D., Chen, Y., & Zhu, Y. (2018) · Cell & Bioscience · doi:10.1186/s13578-018-0200-z · Cited by 83
Assawarachan, S. N., de Bruin, A., Rothuizen, J. J., Penning, L. C., & Schotanus, B. A. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0152 · Cited by 88
Zhong, H., Chen, Y., Li, Y., Chen, R., & Mardon, G. (2015) · Scientific Reports · doi:10.1038/srep08366 · Cited by 81
CRISPR–Cas9 Gene Editing: Curing Genetic Diseases by Inherited Epigenetic Modifications
Kolanu, N. D. (2024) · Global Medical Genetics · doi:10.1055/s-0044-1785234 · Cited by 93
“In a study by Schwank et al, 11 CRISPR – Cas9 was utilized to correct CFTR mutations in intestinal stem cells derived from CF patients.”
MethodHuman Microphysiological Models of Intestinal Tissue and Gut Microbiome
Steinway, S. N., Saleh, J., Koo, B., Delacour, D., & Kim, D. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00725 · Cited by 80
Self-citationApplications of human organoids in the personalized treatment for digestive diseases
Wang, Q., Guo, F., Jin, Y., & Ma, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01194-6 · Cited by 87
“For example, the use of CRISPR gene editing technology to correct CFTR mutations in intestinal organoids of CF patients has shown that gene repair can correct the CFTR locus in patient-derived CF organoids and restore the normal response of organoids to forskolin treatment.(438) Organoids can also be used as an altern…”
BackgroundStem cell-derived intestinal organoids: a novel modality for IBD
Tian, C., Yang, M., Xu, H., Zhu, M., Yue, N.-N., Zhang, Y., Shi, R., Yao, J., Wang, L., Liang, Y.-J., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01556-1 · Cited by 88
“These organoids, if reintroduced into the source patient, may partially cure CF disease [166].”
BackgroundShin, W., Wu, A. T. H., Min, S., Shin, Y. C., Fleming, R., Eckhardt, S., & Kim, H. J. (2020) · iScience · doi:10.1016/j.isci.2020.101372 · Cited by 77
Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy
Yan, Z., Stewart, Z. A., Sinn, P. L., Olsen, J. C., Hu, J., McCray, P. B., & Engelhardt, J. F. (2014) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2014.154 · Cited by 81
“Gene-editing technologies using engineered zinc finger nucleases,(144) transcription activator-like effector nucleases,(145) and clustered regularly interspaced short palindromic repeats/Cas9 nucleases(146) have begun to demonstrate the potential to correct endogenous mutations at the CFTR locus by homologous recombin…”
Shah, V. S., Ernst, S. E., Tang, X. X., Karp, P. H., Parker, C. P., Ostedgaard, L. S., & Welsh, M. J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604905113 · Cited by 78
“Am J Respir Crit Care Med 174(7):787–794.”
BackgroundCRISPR/Cas-Based Modifications for Therapeutic Applications: A Review
Bharathkumar, N., Abraham, S., Meera, P., Aksah, S., Muthu, K., Saravanan, K. M., & Anand, T. (2021) · Molecular Biotechnology · doi:10.1007/s12033-021-00422-8 · Cited by 80
Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications
Yiangou, L., Ross, A., Goh, K. J., & Vallier, L. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.03.016 · Cited by 76
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“Lung organoids have been utilized to model specific disease phenotypes 31,32 and to study infections by respiratory viruses or parasites 33,34 .”
Advances in CRISPR-Cas technology and its applications: revolutionising precision medicine
Azeez, S. S., Hamad, R. S., Hamad, B., Shekha, M. S., & Bergsten, P. (2024) · Frontiers in Genome Editing · doi:10.3389/fgeed.2024.1509924 · Cited by 88
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“For example, this strategy has been employed to correct the CFTR locus in cultured intestinal stem cells of patients with Cystic Fibrosis [9].”
BackgroundMethodInfluentialGenome Editing and Its Applications in Model Organisms
Ma, D., & Liu, F. (2015) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2015.12.001 · Cited by 81
“Their data indicated that the corrected allele could be detected and was confirmed to be functional [77].”
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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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