Transposable vectors for dystrophin-expression in a murine model for muscular dystrophy
Prof. Nicolas Mermod, Institute of Biotechnology, University of Lausanne
Abstract
Current gene transfer approaches for potential curative treatments of muscle diseases like the Duchenne muscular dystrophy are limited by difficulties in reaching a systemic muscle treatment including the heart and diaphragm, by the inability of current vectors to express a full length dystrophin, and by the immune response against viral vectors. We have previously identified non-viral vectors based on the piggyBac transposon that are capable of efficiently mediating gene transfer and sustained GFP expression in mesoangioblast muscle precursor cells and in murine muscles in vivo. Taken together with the favorable genomic integration preference of this transposon, and with the very large cargo size that it can accommodate, this now prompts us to evaluate its performance for dystrophin expression in the Duchenne mdx mice model, and to assess a possible improvement of muscle function, for instance using the atomic force microscopy-based assay that we recently devised.
We also plan to profile the vector’s genomic integration profile using next-generation DNA sequencing, to further evaluate and document its reported preference for integration at non-coding genomic loci. With this approach, we hope to provide a strategy that may allow the expression of very large coding sequences in muscles, as needed to treat all patients with Duchenne muscular dystrophy, with the perspective to progress towards larger animal models.
Lay summary
Le développement de nouvelles thérapies géniques, pour des maladies telles que la dystrophie musculaire de Duchenne, nécessite l’introduction d’un gène thérapeutique dans des muscles du corps entier, y compris le cœur et le diaphragme. Ce type d’approche thérapeutique est actuellement limité par des blocages technologiques, notamment pour le transfert d’une grande séquence d’ADN couvrant la longueur entière de la protéine dystrophine, et par la réponse immunitaire contre certaines protéines d’origine virale qui aide l’ADN thérapeutique à s’intégrer dans les cellules. Nous avons précédemment identifié un système non-viral basé sur un « gène sauteur » du papillon appelé transposon piggyBac. Nos travaux préalables ont montré que ce système permet de transférer efficacement des gènes tests dans les cellules souches du muscle in vitro, et aussi dans les muscles de souris après injection intramusculaire. Durant ce projet, nous allons évaluer les performances de ce système pour restaurer l'expression de la dystrophine dans les muscles de souris affectées par la dystrophie musculaire de Duchenne. Nous évaluerons une possible amélioration du maintient de la fonction musculaire, notamment en utilisant un test que nous avons récemment mis au point basé sur la microscopie à force atomique. Nous prévoyons également de déterminer les sites d'intégration chromosomique du gène thérapeutique par séquençage d'ADN à haut débit, afin d'évaluer et de documenter son intégration préférentielle en dehors des gènes de la cellule. Durant ce projet, nous espérons développer une méthode permettant de restaurer la fabrication de la protéine dystrophine manquante chez la souris dystrophique, permettant ainsi de maintenir une bonne fonction musculaire, avec comme perspective des essais thérapeutiques sur des modèles animaux plus proches de l’homme.
Projets
- Nouveaux projets de recherche dès 2024
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