Deep dive into the science behind Pompe treatments

Last updated Sept. 10, 2024, by Marisa Wexler, MS
Fact-checked by Patrícia Silva, PhD

Enzyme replacement therapy, or ERT, is a type of medication used in the treatment of Pompe disease. Currently, ERT is the only approved treatment for Pompe that addresses the disease’s underlying cause.

Although ERT is not a cure for Pompe — and there are some challenges and limitations with this type of treatment — ERT can help to slow the disease’s progression, allowing people to live longer and retain better functionality.

General mechanism of action of ERT

In simple terms, enzymes are proteins promoting certain chemical reactions that put together new molecules or break apart old molecules. Within the body, there are constantly millions of chemical reactions taking place as molecules are made, used, and reorganized. Most of these chemical reactions can only happen because of an enzyme that promotes or facilitates such reactions.

There are thousands of enzymes naturally made in the body and each of them has a specific purpose. For example, one enzyme might only break apart a specific type of molecule, while a separate enzyme would be needed to put that same molecule back together.

By regulating the precise amount and activity of various enzymes, the body’s cells can fine-tune their molecular activity, ensuring each cell has just the right amount of every type of molecule.

The instructions for making enzymes are stored in genes in a cell’s DNA. Many genetic diseases, including Pompe disease, are caused by mutations in genes that provide the instructions to make a specific enzyme. As a result of these mutations, cells are unable to produce a working version of the enzyme and instead either make a dysfunctional enzyme or no enzyme at all.

Without a working version of the specific enzyme, cells are unable to promote the specific chemical reaction that particular enzyme is responsible for, which can have dire impacts on cells’ health.

Enzyme replacement therapy, as the name suggests, is a treatment strategy that aims to replace a missing or defective enzyme by providing cells with a functional version of that enzyme. ERTs are a mainstay of treatment for many genetic disorders associated with enzyme deficiencies, including Pompe disease.

ERT use in Pompe disease

Pompe disease is a genetic disorder caused by mutations in the gene that provides instructions to make an enzyme called acid alpha-glucosidase (GAA), leading to absence or dysfunction of this enzyme. Cells normally use the GAA enzyme to help regulate levels of glycogen, a complex sugar molecule.

Glycogen is a polymer of a simple sugar molecule called glucose. In other words, one glycogen molecule is a long chain of many individual glucose molecules that have all been attached to one another. Glucose is the main sugar molecule the body burns to generate energy.

Because glycogen is essentially a long string of glucose, it can normally act as a useful way to store a significant amount of glucose molecules in a relatively compact space. When the cell requires energy, it can break off individual glucose molecules to burn. Glycogen is especially important for muscle cells, which normally need a lot of energy to help facilitate the body’s movement.

GAA is the enzyme that’s responsible for breaking down glycogen into individual molecules of glucose. But in people with Pompe disease, GAA doesn’t work correctly. As a result, cells are unable to break down long glycogen molecules into individual pieces of glucose.

People with Pompe do have all the other enzymes that are responsible for making glycogen, so their cells are still able to make glycogen for energy storage. But because they cannot break that glycogen down, it continuously builds up within cells, especially muscle cells.

The buildup of glycogen eventually reaches toxic levels, damaging cells. The resulting cellular damage is what drives the symptoms of Pompe disease.

ERT for Pompe disease provides a person’s cells with a working version of the GAA enzyme. Having this version of the enzyme means glycogen molecules can be broken down, which can help to counteract the toxic buildup of glycogen and slow the progression of Pompe disease.

While there are a few different types of Pompe ERT, all of them work via this same basic mechanism.

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