Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat model

Audrey Bourdon, Virginie François, Liwen Zhang, Aude Lafoux, Bodvael Fraysse, Gilles Toumaniantz, Thibaut Larcher, Tiphaine Girard, Mireille Ledevin, Cyrielle Lebreton, Agnès Hivonnait, Anna Creismeas, Marine Allais, Basile Marie, Justine Guguin, Véronique Blouin, Séverine Remy, Ignacio Anegon, Corinne Huchet, Alberto MalerbaBetty Kao, Anita Le Heron, Philippe Moullier, George Dickson, Linda Popplewell, Oumeya Adjali, Federica Montanaro, Caroline Le Guiner

Research output: Contribution to journalArticlepeer-review


Duchenne muscular dystrophy (DMD) is a muscle wasting disorder caused by mutations in the gene encoding dystrophin. Gene therapy using micro-dystrophin (MD) transgenes and recombinant adeno-associated virus (rAAV) vectors hold great promise. To overcome the limited packaging capacity of rAAV vectors, most MD do not include dystrophin carboxy-terminal (CT) domain. Yet, the CT domain is known to recruit α1- and β1-syntrophins and α-dystrobrevin, a part of the dystrophin-associated protein complex (DAPC), which is a signaling and structural mediator of muscle cells. In this study, we explored the impact of inclusion of the dystrophin CT domain on ΔR4-23/ΔCT MD (MD1), in DMDmdx rats, which allows for relevant evaluations at muscular and cardiac levels. We showed by LC-MS/MS that MD1 expression is sufficient to restore the interactions at a physiological level of most DAPC partners in skeletal and cardiac muscles, and that inclusion of the CT domain increases the recruitment of some DAPC partners at supra-physiological levels. In parallel, we demonstrated that inclusion of the CT domain does not improve MD1 therapeutic efficacy on DMD muscle and cardiac pathologies. Our work highlights new evidences of the therapeutic potential of MD1 and strengthens the relevance of this candidate for gene therapy of DMD.

Original languageEnglish
JournalGene Therapy
Early online date1 Feb 2022
Publication statusPublished - 2022
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported by the MDA (Muscular Dystrophy Association, Research Grant ID #513878), the AFM-Téléthon (Association Française contre les Myopathies), the “Fondation d’entreprise pour la thérapie génique en Pays de la Loire”, INSERM, INRA, the University of Nantes and the University Hospital of Nantes. The Fusion Orbitrap instrument used for proteomics study was supported by NIH Award Number Grant S10 OD018056.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.


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