Beneficial effect of gene therapy in model mice of LGMD R1 linked to calpain

Six gene therapy programs are under development in girdle myopathies (LGMD) at Sarepta Therapeutics, in collaboration with the Nationwide Chidren’s Hospital (Columbus, USA). They concern LGMD R1 linked to calpain, LGMD R5 linked to γ-sarcoglycan, LGMD R12 linked to anoctamine, LGMD R2 linked to dysferlin, LGMDR3 linked to α-sarcoglycan and LGMDR4 linked to β-sarcoglycan, the last three are already in the clinical trial phase. They are all based on the same construction associating an AAVrh74 vector with an MCK promoter which specifically targets muscle and with the normal human gene replacing the defective gene. 

In LGMD R1 linked to calpain, the product “AAVrh74.tMCK.hCAPN3” was developed and studied by a team of Jerry Mendell (Nationwide Chidren’s Hospital, Columbus, United States) to replace the calpain 3 gene, protein missing in this form of LGMD. Systemic injection of two doses (strong and weak) of this product has been evaluated in two mouse models with asymptomatic LGMD R1 2 and 5 months old. The results obtained after a 5-month follow-up show, whatever the dose and the age of the mice, the effectiveness of the product both functionally and physiologically or histopathologically: improvement of endurance on a treadmill, better contractility of the muscles, increase in the size of muscle fibers and absence of cardiotoxicity. 


Systemic delivery of AAVrh74.tMCK.hCAPN3 rescues the phenotype in a mouse model for LGMD2A/R1. Sahenk Z, Ozes B, Murrey D et al. Molecular Therapy – Methods & Clinical Development