Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A
Lostal et al., Sci. Transl. Med. 11, eaat6072 (2019) 27 Novembre 2019
Author: William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg1, Heather Best1, John Edward Smith, Jochen Gohlke, Guillaume Corre, Xidan Li, Zaher Elbeck, Ralph Knöll, Jack-Yves Deschamps, Henk Granzier, Isabelle Richard
Lateral muscular dystrophy type 2A (LGMD 2A or LGMDR1) is a neuromuscular disease caused by mutations in the calpain 3 (CAPN3) gene . Preliminary experiments of calpain3 gene transfer mediated by adenoviral-associated vectors (AAVs) have shown cardiotoxicity with ectopic expression of the calpain 3 transgene.
In this study, we performed a preliminary dose study in a mouse model of severe muscular dystrophy, double knock out for both calpain 3 and dysferlin.
We also evaluated the safety and biodistribution of administration of the AAV9-desmin-hCAPN3a vector to nonhuman primates (NHPs) with a dose of 3 X 10 13 viral genome/kg.
Administration of the vector caused no detectable adverse effects or toxicity in NHPs. Of note, expression of the transgene did not cause any cardiac morphological or functional abnormalities in the injected animals and achieved therapeutic expression in skeletal muscle.
Further studies about the cause of cardiotoxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest a species-specific splicing of titin.
Mice have reduced calpain-3 buffering capacity in comparison to nonhuman primates and humans.
Our studies highlight a complex interaction between calpain-3 and titin and demonstrate an effective and safe role for systemic delivery of calpain-3 via an adenoviral vector (AAV9-desmin-hCAPN3a) in nonhuman primates, providing adequate support for potential calpain-3 gene therapy in humans.
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