A team of scientists has discovered that treatment combining gene transfer with pharmacological chaperones is superior to enzyme replacement therapy (ERT) in boosting levels of the lysosomal enzyme acid alpha-glucosidase (GAA) in mouse models of Pompe disease (PD), resulting in improved rescue of the Pompe disease phenotype. The findings were published in Nature Communications.

Pompe disease is characterized by decreased GAA activity, which leads to the pathological accumulation of glycogen. This alters lysosomal function and cell metabolism. At present, the standard treatment of Pompe disease is ERT with intravenous infusions of recombinant human GAA (rhGAA). 

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Another treatment option is gene therapy with adeno-associated virus (AAV) vectors. Costa-Verdera and colleagues have studied the efficacy of this treatment method. They reported, “We previously showed that AAV vector-mediated hepatic expression of a secretable form of GAA can correct the [Pompe disease] phenotype in mice.” 

The research team conducted a study to compare the efficacy of the 2 treatments in mouse models. They generated a colony of immunodeficient Gaa−/− mice and performed long-term, biweekly rhGAA infusions in these mice to compare the therapeutic efficacy of AAV gene transfer against that of ERT.

The results showed that AAV gene transfer drove superior rescue of the Pompe disease phenotype compared to ERT in the following ways:

  • Higher GAA activity levels in the heart and skeletal muscles
  • Lower glycogen accumulation in the brain and spinal cord
  • Higher GAA bioavailability in the skeletal muscles.

They also discovered that pharmacological chaperones enhanced the efficacy of gene transfer. The researchers concluded, “Our data indicate that gene transfer provides superior enzyme bioavailability to refractory tissues, including [central nervous system], in mice, resulting in superior therapeutic efficacy compared to ERT.”

Although not a cure, the introduction of ERT has significantly transformed the treatment landscape of PD. “ERT with rhGAA has shown to resolve cardiomyopathy and improve the survival of [infantile-onset PD] subjects, as well as to improve and/or stabilize the disease progression in [late-onset PD] subjects,” the study team wrote.


Costa-Verdera H, Collaud F, Riling CR, et al. Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primatesNat Commun. 2021;12(1):6393. doi:10.1038/s41467-021-26744-4