Preclinical efficacy of a gene therapy for CHKB-mediated muscular dystrophy.

Loss-of-function variants of the CHKB gene cause an autosomal recessive disease described as an early onset congenital megaconial (large peripheral mitochondria) muscular dystrophy. CHKB encodes choline kinase β, the first enzyme in the biochemical pathway for synthesis of the major membrane phospholipid phosphatidylcholine. Chkb -/- mice recapitulate the human disease with affected skeletal muscle displaying a decrease in strength, myofiber atrophy, megaconial mitochondria, fat accumulation within muscle cells, and an increase in muscle injury. Here, we assessed the therapeutic potential of an AAV therapy for the treatment of CHKB-mediated muscular dystrophy. Chkb -/- mice were injected once suborbitally with three different doses of recombinant AAV9 (rAAV9) encoding human CHKB under control of a constitutive and ubiquitous promoter (AAV9-CHKB). The AAV9-CHKB-treated mice were biochemically and phenotypically indistinguishable from the wild type mice. In the Chkb -/- mouse model, all doses resulted in expression of the CHKB protein and restored choline kinase β enzyme activity, body and muscle weight, and normal muscle cell physiology, and they prevented lipid metabolism imbalance and increased the capacity to walk. These findings point to AAV9-mediated gene therapy as a potential treatment for CHKB-mediated disease.