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

William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg, Heather Best, John Edward Smith, Jochen Gohlke, Guillaume Corre, Xidan Li, Zaher Elbeck, Ralph Knöll, Jack Yves Deschamps, Henk Granzier, Isabelle Richard

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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.

Original languageEnglish (US)
Article numbereaat6072
JournalScience Translational Medicine
Issue number520
StatePublished - Nov 27 2019


ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lostal, W., Roudaut, C., Faivre, M., Charton, K., Suel, L., Bourg, N., Best, H., Smith, J. E., Gohlke, J., Corre, G., Li, X., Elbeck, Z., Knöll, R., Deschamps, J. Y., Granzier, H., & Richard, I. (2019). Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A. Science Translational Medicine, 11(520), [eaat6072]. https://doi.org/10.1126/scitranslmed.aat6072