Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy.

[en] Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.

Disciplines :

Neurology

Author, co-author :

Le Guiner, Caroline

Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques > Neuropédiatrie

Montus, Marie

Larcher, Thibaut

Fraysse, Bodvael

Moullec, Sophie

Allais, Marine

Francois, Virginie

Dutilleul, Maeva

Malerba, Alberto

More authors (25 more)

Language :

English

Title :

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy.

Publication date :

July 2017

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Volume :

Pages :

16105

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 14 February 2018

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