Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids
Summary: Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drug...
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Elsevier
2025-03-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225002391 |
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| author | Lucia Nicosia Iwona Pranke Roberta V. Latorre Joss B. Murray Lisa Lonetti Kader Cavusoglu-Doran Elise Dreano James P. Costello Michael Carroll Paola Melotti Claudio Sorio Isabelle Sermet-Gaudelus Martina F. Scallan Patrick T. Harrison |
| author_facet | Lucia Nicosia Iwona Pranke Roberta V. Latorre Joss B. Murray Lisa Lonetti Kader Cavusoglu-Doran Elise Dreano James P. Costello Michael Carroll Paola Melotti Claudio Sorio Isabelle Sermet-Gaudelus Martina F. Scallan Patrick T. Harrison |
| author_sort | Lucia Nicosia |
| collection | DOAJ |
| description | Summary: Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores the use of adenine base editing to edit G542X to a non-CF-causing variant, G542R, and recover CFTR function. Using base editor engineered virus-like particles (BE-eVLPs) in patient-derived intestinal organoids, we achieved ∼2% G542X-to-G542R editing efficiency and restored CFTR-mediated chloride transport to ∼6.4% of wild-type levels, independent of modulator treatment, and with no bystander edits. This proof-of-principle study demonstrates the potential of base editing to rescue G542X and provides a foundation for future in-vivo applications. |
| format | Article |
| id | doaj-art-36d2ac43cc19488d977102bf373cd18c |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-36d2ac43cc19488d977102bf373cd18c2025-08-20T01:58:28ZengElsevieriScience2589-00422025-03-0128311197910.1016/j.isci.2025.111979Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoidsLucia Nicosia0Iwona Pranke1Roberta V. Latorre2Joss B. Murray3Lisa Lonetti4Kader Cavusoglu-Doran5Elise Dreano6James P. Costello7Michael Carroll8Paola Melotti9Claudio Sorio10Isabelle Sermet-Gaudelus11Martina F. Scallan12Patrick T. Harrison13Department of Physiology, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, IrelandINSERM, CNRS, Institut Necker Enfants Malades, Paris, France; Université Paris-Cité, Paris, FranceDepartment of Medicine, University of Verona, Verona, ItalyDepartment of Physiology, University College Cork, Cork, IrelandDepartment of Physiology, University College Cork, Cork, IrelandDepartment of Physiology, University College Cork, Cork, IrelandINSERM, CNRS, Institut Necker Enfants Malades, Paris, France; Université Paris-Cité, Paris, FranceSchool of Microbiology, University College Cork, Cork, IrelandSchool of Microbiology, University College Cork, Cork, IrelandCystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, ItalyDepartment of Medicine, University of Verona, Verona, ItalyINSERM, CNRS, Institut Necker Enfants Malades, Paris, France; Université Paris-Cité, Paris, France; Cystic Fibrosis National Pediatric Reference Center, Pneumo-Allergologie Pédiatrique, Hôpital Necker Enfants Malades, , Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; European Reference Network, ERN-Lung CF, Frankfurt am Mein, GermanySchool of Microbiology, University College Cork, Cork, IrelandDepartment of Physiology, University College Cork, Cork, Ireland; Division of Pulmonary Medicine, Cincinnati Children’s Hospital, Cincinnati, OH, USA; Corresponding authorSummary: Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores the use of adenine base editing to edit G542X to a non-CF-causing variant, G542R, and recover CFTR function. Using base editor engineered virus-like particles (BE-eVLPs) in patient-derived intestinal organoids, we achieved ∼2% G542X-to-G542R editing efficiency and restored CFTR-mediated chloride transport to ∼6.4% of wild-type levels, independent of modulator treatment, and with no bystander edits. This proof-of-principle study demonstrates the potential of base editing to rescue G542X and provides a foundation for future in-vivo applications.http://www.sciencedirect.com/science/article/pii/S2589004225002391Health sciencesClinical geneticsCellular therapyGenetic engineering |
| spellingShingle | Lucia Nicosia Iwona Pranke Roberta V. Latorre Joss B. Murray Lisa Lonetti Kader Cavusoglu-Doran Elise Dreano James P. Costello Michael Carroll Paola Melotti Claudio Sorio Isabelle Sermet-Gaudelus Martina F. Scallan Patrick T. Harrison Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids iScience Health sciences Clinical genetics Cellular therapy Genetic engineering |
| title | Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids |
| title_full | Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids |
| title_fullStr | Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids |
| title_full_unstemmed | Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids |
| title_short | Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids |
| title_sort | adenine base editing with engineered virus like particles rescues the cftr mutation g542x in patient derived intestinal organoids |
| topic | Health sciences Clinical genetics Cellular therapy Genetic engineering |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225002391 |
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