Species-specific titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy 2A - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Science Translational Medicine Année : 2019

Species-specific titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy 2A

William Lostal
  • Fonction : Auteur
Carinne Roudaut
Marine Faivre
  • Fonction : Auteur
Karine Charton
Laurence Suel
Nathalie Bourg
Heather Best
  • Fonction : Auteur
John Edward Smith
  • Fonction : Auteur
Jochen Gohlke
  • Fonction : Auteur
Guillaume Corre
Xidan Li
  • Fonction : Auteur
Zaher Elbeck
  • Fonction : Auteur
Ralph Knöll
  • Fonction : Auteur
Isabelle Richard

Résumé

Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene (CAPN3). Previous experiments using adeno-associated viral (AAV) vector-mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Here, we performed a preliminary dose study in a severe double-knockout mouse model deficient in calpain 3 and dysferlin. We evaluated safety and biodistribution of AAV9-desmin-hCAPN3 vector administration to nonhuman primates (NHPs) with a dose of 3 × 1013 viral genomes/kg. Vector administration did not lead to observable adverse effects or to detectable toxicity in NHP. Of note, the transgene expression did not produce any abnormal changes in cardiac morphology or function of injected animals while reaching therapeutic expression in skeletal muscle. Additional investigation on the underlying causes of cardiac toxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest species-specific titin splicing. Mice have a reduced capacity for buffering calpain 3 activity compared to NHPs and humans. Our studies highlight a complex interplay between calpain 3 and titin binding sites and demonstrate an effective and safe profile for systemic calpain 3 vector delivery in NHP, providing critical support for the clinical potential of calpain 3 gene therapy in humans.

Dates et versions

hal-02408897 , version 1 (13-12-2019)

Identifiants

Citer

William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, et al.. Species-specific titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy 2A. Science Translational Medicine, 2019, 11 (520), pp.eaat6072. ⟨10.1126/scitranslmed.aat6072⟩. ⟨hal-02408897⟩
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