Precision medicine in action for Pompe disease

Antonietta Tarallo, Giancarlo Parenti, Nicola Brunetti-Pierri

Glycogen storage disease type II, more often referred to as Pompe disease, is an inherited metabolic disorder caused by deficiency of lysosomal acid ?-glucosidase (GAA). The disease primarily affects skeletal and cardiac muscles. Patients are classified as having infantile-onset Pompe disease (IOPD) or late-onset Pompe disease (LOPD) based on the age at which clinical manifestations appear. More than 650 pathogenic variants in the gene encoding GAA have been reported. While the intronic variant c.-32-13T>G is found in approximately 80%–90% of patients with LOPD, most patients carry private variants. Enzyme replacement therapy (ERT) for Pompe disease has markedly improved patient survival, but central nervous system involvement refractory to ERT has been observed in aging patients.1 Despite initial improvement after the initiation of ERT, some patients show clinical decline, and muscle involvement is resistant to treatment. Furthermore, the recombinant enzyme used for ERT is immunogenic, and patients who are cross-reactive immune material negative are especially at risk of developing anti-GAA antibodies that result in decreased ERT efficacy or severe immune reactions. The limitations of ERT have driven the development of several preclinical studies and ongoing gene therapy clinical trials for LOPD and IOPD.

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