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Congenital muscular dystrophy with megaconial myopathy (MDCMC) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. The observation of megamitochondria in skeletal muscle biopsies is exclusive to this type of MD. The disease is caused by loss of function mutations in the choline kinase beta ( CHKB ) gene which results in dysfunction of the Kennedy pathway for the synthesis of phosphatidylcholine. We have previously reported a rostrocaudal MD ( rmd ) mouse with a deletion in the  Chkb  gene resulting in an MDCMC-like phenotype, and we used this mouse to test gene therapy strategies for the rescue and alleviation of the dystrophic phenotype. Introduction of a muscle-specific  Chkb  transgene completely rescues motor and behavioral function in the  rmd  mouse model, confirming the cell-autonomous nature of the disease. Intramuscular gene therapy post-disease onset using an adeno-associated viral 6 (AAV6) vector carrying a functional copy of  Chkb  is also capable of rescuing the dystrophy phenotype. In addition, we examined the ability of choline kinase alpha ( Chka ), a gene paralog of  Chkb , to improve dystrophic phenotypes when upregulated in skeletal muscles of  rmd  mutant mice using a similar AAV6 vector. The sum of our results in a preclinical model of disease suggest that replacement of the  Chkb  gene or upregulation of endogenous  Chka  could serve as potential lines of therapy for MDCMC patients.

Functional rescue in a mouse model of congenital muscular dystrophy with megaconial myopathy