Scientists Create Stabilizers to Boost Pompe Disease ERT Effectiveness

The new molecules work on the GAA enzyme to reduce glycogen buildup

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Researchers in Taiwan have developed new molecules that can stabilize the acid alpha-glucosidase (GAA) enzyme, a strategy they say might improve the effectiveness of treatments for Pompe disease.

Their study, “Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-glucosidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease,” was published in Bioorganic & Medicinal Chemistry.

Pompe disease is caused by mutations in the gene that provides instructions for making the GAA enzyme, resulting in little or none being produced. The enzyme breaks down the complex sugar molecule glycogen, which builds up to toxic levels inside cells without GAA.

The current standard of care treatment for Pompe is enzyme replacement therapy (ERT), which involves an infusion of a version of the enzyme.

One of the limitations of current ERT approaches is that the GAA enzyme, which normally does its job in highly acidic cellular compartments called lysosomes, is not very stable in the blood. To be therapeutically effective, high doses are often needed to get enough of the enzyme to cells, but higher doses increase the risk of side effects.

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A team of scientists worked to create small molecules that can stabilize GAA, allowing more of the functional enzyme to get into cells where it’s needed.

“Developing small molecules to maintain protein function and to suppress the unavoidable destabilization of the [GAA] protein is an attractive approach to improve ERT efficacy,” the researchers wrote.

To create a stabilizer, they started with a molecule called ADMDP (2-aminomethyl polyhydroxylated pyrrolidine).

Using 16 chemical variations of ADMDP, they gradually increased the temperature to see when the GAA enzyme’s structure was disrupted. When the enzyme is more stable, it can function at higher temperatures.

The initial screen identified two ADMDP versions with promising stabilizing effects. Using these, the researchers made a series of slight chemical modifications, continually testing them to assess stabilizing properties.

The scientists at last identified one compound as the most promising, dubbing it stabilizer 21. It and related compounds bind to the same GAA region as glycogen, analyses showed.

In cell experiments, co-treatment with GAA and stabilizer 21 led to a dose-dependent increase in enzyme activity at five times GAA treatment alone. Higher enzyme activity used with stabilizer 21 was sustained over nine days, “indicating that co-treatment is able to prolong therapeutic activity and potentially amend [Pompe disease] patient treatment,” the scientists wrote, noting this method enhances the effectiveness of ERT because the dosage would be reduced, “a benefit resulting in economic usage of expensive protein drug and avoiding the severe humoral immune response, resulting in infusion-associated reactions.”

A small proof-of-concept experiment also indicated that co-treatment with stabilizer 21 increased enzyme activity in mice.

“In a cell-based [Pompe disease] model, co-treatment of [stabilizer] 21 with [GAA] significantly improved (up to 5-fold) intracellular activity and reduced the glycogen content, compared to the administration of [GAA] alone (ERT),” the researchers wrote, noting this effect was confirmed with “preliminary animal studies” and calling for more research.