Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids

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 <i>in</i> <i>-</i> <i>vivo</i> applications.

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Publication Details

Journal
iScience
Published
2025-02-21
DOI
https://doi.org/10.1016/j.isci.2025.111979
Citations
8
Primary Topic
CRISPR and Genetic Engineering
Type
article
Field-Weighted Citation Impact
6.45

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article

Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids

Paola Melotti, Isabelle Sermet‐Gaudelus, Lucia Nicosia, Ramón Latorre et al.
8 citations
iScience
CRISPR and Genetic Engineering
6.45
article

Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids

Paola Melotti, Isabelle Sermet‐Gaudelus, Lucia Nicosia, Ramón Latorre, Patrick T. Harrison, Kader Cavusoglu-Doran, Michael Carroll, Elise Dréano, Iwona Pranke, Joseph T. Costello, Martina Scallan, Claudio Sorio, L. Lonetti, Joss B. Murray
article en
8 citations

Abstract

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 <i>in</i> <i>-</i> <i>vivo</i> applications.

iScienceVol. 28(3)
University of Verona (IT), Cincinnati Children's Hospital Medical Center (US), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), University College Cork (IE), Institut Necker Enfants Malades (FR), Azienda Ospedaliera Universitaria Integrata Verona (IT), Assistance Publique – Hôpitaux de Paris (FR), ERN GUARD-Heart (NL)
Cystic Fibrosis Foundation, Cystic Fibrosis Trust
Zero hunger
Openalex Percentile: Top 3%
CRISPR and Genetic Engineering
6.45
DOIOpen Access PDFOpenAlex
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