Researchers at Codexis Inc. engineered new α-glucosidase (GAA) enzyme variants that are substantially more stable than wild-type GAA. One or more of these variants could be better taken up by cells when used as enzyme replacement therapy (ERT) for Pompe disease, according to the researchers.

Their high activity may also persist longer if used as gene therapy. ERT with recombinant human GAA is approved for the treatment of Pompe disease, which is characterized by GAA enzyme deficiency.

“We believed that these evolved GAA variants will inspire a new generation of enzyme replacements or gene therapies with the ultimate goal of improving outcomes in patients with Pompe disease,” they wrote in a poster they are presenting at the NORD Breakthrough Summit 2021.

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However, the efficacy of the treatment is limited due to the enzyme’s short half-life in circulation, instability in neutral pH, and poor uptake into muscles. This means that very high doses of the enzyme must be administered frequently.

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To overcome these limitations and to reduce any predicted immunogenic epitopes on the recombinant enzyme, the team of researchers led by Gjalt Huisman, PhD, used Codexis’ protein engineering technology called CodeEvolver to develop new and improved recombinant GAA enzymes. 

They screened more than 19,000 variants and found that the engineered variants were more efficiently expressed, more stable at neutral pH and in plasma, and more rapidly and efficiently taken up by cells and trafficked to the lysosome, which is where they are needed.

The researchers are continuing to evaluate the evolved GAA variants in a mouse model of Pompe disease and anticipate that the improvements they achieved could be translated into the clinic in the future to treat patients with the disease.

Codexis is a protein engineering company that specializes in developing enzymes for pharmaceutical, food, and medical uses. 


Overcoming α-glucosidase deficiencies with protein engineering to develop next-generation Pompe disease therapeutics. Poster presented at: NORD Breakthrough Summit 2021: October 18-19, 2021; Virtual.