A Mouse Model of X-Linked Chronic Granulomatous Disease for the Development of CRISPR/Cas9 Gene Therapy.
Genes (Basel)
; 15(6)2024 May 28.
Article
de En
| MEDLINE
| ID: mdl-38927642
ABSTRACT
Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease mainly caused by mutations in the X-linked CYBB gene that abrogate reactive oxygen species (ROS) production in phagocytes and microbial defense. Gene repair using the CRISPR/Cas9 system in hematopoietic stem and progenitor cells (HSPCs) is a promising technology for therapy for CGD. To support the establishment of efficient and safe gene therapies for CGD, we generated a mouse model harboring a patient-derived mutation in the CYBB gene. Our CybbC517del mouse line shows the hallmarks of CGD and provides a source for Cybb-deficient HSPCs that can be used to evaluate gene-therapy approaches in vitro and in vivo. In a setup using Cas9 RNPs and an AAV repair vector in HSPCs, we show that the mutation can be repaired in 19% of treated cells and that treatment restores ROS production by macrophages. In conclusion, our CybbC517del mouse line provides a new platform for refining and evaluating novel gene therapies and studying X-CGD pathophysiology.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Thérapie génétique
/
Modèles animaux de maladie humaine
/
Systèmes CRISPR-Cas
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NADPH Oxidase 2
/
Granulomatose septique chronique
Limites:
Animals
/
Humans
Langue:
En
Journal:
Genes (Basel)
Année:
2024
Type de document:
Article
Pays d'affiliation:
Allemagne