According to a new study published in Medical Hypotheses, α-glucosidase with a high specific activity can efficiently break down the accumulated glycogen in the tissue of patients with Pompe disease. The study highlighted that α-glucosidase with a high turnover number could reduce the required dosage for treatment and potentially lower the treatment cost.

The study further suggested that similar screening strategies can be employed to identify high-specific activity mutants of other enzymes involved in lysosomal storage diseases for enzyme replacement therapy.

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The only approved treatment for late-onset and classical infantile-onset Pompe disease is Enzyme Replacement Therapy (ERT) with recombinant human GAA (rhGAA) administered intravenously. rhGAA was approved by the US Food and Drug Administration and European Medicines Agency in 2006. 

Alternative therapies such as pharmacological chaperone, substrate reduction, and gene therapy are yet to be approved for PD. Although there have been attempts to enhance various properties of rhGAA protein, there are no reports of mutants with high specific activity for this enzyme, the researchers noted.

The article proposed a phenotype-based screening method employing saccharomyces cerevisiae to identify high-specific activity mutants of rhGAA through the complementation of yeast maltase with human GAA, followed by the yeast strain’s ability to grow on low maltose concentrations.

“I propose that high-specific activity mutants of GAA can confer a clinical advantage to the recombinant protein to overcome some of the limitations of the currently approved enzyme replacement therapies, “the author highlighted.

The author highlighted that a mutant GAA protein with higher specific activity would more efficiently break down glycogen’s glycosidic bonds when administered intravenously than the wild-type version.

This can make way for ERT to be an alternative treatment option for Pompe disease patients in the absence of other approved therapies. The adjunctive treatments for ERT include nutrition, exercise, immunomodulation, and upregulation of mannose-6-phosphate receptor expression.

Besides adjunctive therapies, engineered variants of rhGAA that improve bioavailability, stability, and uptake can also be effective for ERT treatment. However, the standard dosage of ERT with rhGAA is 20 mg/kg every other week, which increases treatment costs and the amount of protein required for therapy.

One cannot rule out the possibility of selecting mutants of GAA imparting growth to the yeast strain by virtue of increased stability or a combination of turnover number and stability, with the yeast screening strategy described here,” the authors wrote.


Lakshminarasimhan A. High-specific activity variants of recombinant human α-glucosidase for the treatment of Pompe disease. Medical Hypotheses. Published online March 11, 2023, doi: 10.1016/j.mehy.2023.111044