Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A - Université d'Évry Access content directly
Journal Articles Science Translational Medicine Year : 2019

Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A

John Edward Smith
  • Function : Author
Jochen Gohlke
  • Function : Author
Xidan Li
  • Function : Author
Zaher Elbeck
  • Function : Author
Ralph Knöll
  • Function : Author
Jack-Yves Deschamps
  • Function : Author
Henk Granzier
  • Function : Author

Abstract

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 × 10 13 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 and versions

hal-03335723 , version 1 (06-09-2021)

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William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, et al.. Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A. Science Translational Medicine, 2019, 11 (520), pp.eaat6072. ⟨10.1126/scitranslmed.aat6072⟩. ⟨hal-03335723⟩
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