Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy.

We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of “extra-lysosomal” events including defective autophagy and disruption of a variety of signaling pathways. Here, we report that metabolic abnormalities and energy deficit also contribute to the complexity of the pathogenic cascade. A decrease in the metabolites of the glycolytic pathway and a shift to lipids as the energy source are observed in the diseased muscle.

We now demonstrate in a pre-clinical study that a recently developed replacement enzyme (recombinant human GAA; AT-GAA; Amicus Therapeutics) with much improved lysosome-targeting properties reversed or significantly improved all aspects of the disease pathogenesis, an outcome not observed with the current standard of care. The therapy was initiated in GAA-deficient mice with fully developed muscle pathology but without obvious clinical symptoms; this point deserves consideration.

Keywords: Pompe disease, enzyme replacement therapy, lysosomal targeting, mTORC1/AMPK signaling, metabolome, muscle, autophagy, acid alpha glucosidase, glycogen

Mol Ther Methods Clin Dev. 2020 Sep 11; 18: 199–214. Published online 2020 Jun 10. doi: 10.1016/j.omtm.2020.05.026

PMCID: PMC7334420

PMID: 32671132