Chaperone therapy for Fabry disease

Last updated April 19, 2024, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

Chaperone therapy is one of two main strategies currently used to treat Fabry disease, a genetic disorder marked by the toxic buildup of fatty molecules inside cells.

The disease is caused by mutations in the GLA gene, which provides instructions for making the alpha-galactosidase A (GLA) enzyme. This enzyme is necessary for breaking down fatty molecules, mainly globotriaosylceramide (Gb3), into building blocks that cells can use.

GLA deficiency in Fabry disease results in the accumulation of these fat molecules to toxic levels inside cells, causing organ damage and the disease’s symptoms.

Currently, only two classes of therapies are approved for Fabry: enzyme replacement therapy, which works by regularly supplying the missing enzyme to patients, and chaperone therapy, which stabilizes the existing enzyme to improve its function.

What is chaperone therapy?

Chaperones are naturally occurring proteins that assist in various cellular processes, such as the correct folding and stabilization of other proteins. They act as molecular guardians, ensuring other proteins are properly folded and functional, and are transported to their correct location within cells — sort of like a chaperone driving someone where they need to go.

Chaperone therapy is a strategy that uses small molecules that mimic the function of natural chaperones. These pharmacological chaperones can similarly help correct or stabilize misfolded or malfunctioning proteins in the body.

While the GLA enzyme can function correctly only inside a cellular compartment called the lysosome, the abnormal protein that is produced in Fabry patients is degraded prematurely by the cell’s quality control mechanisms before it can reach these organelles. By stabilizing the mutated GLA enzyme and helping it to fold correctly, chaperone therapy can help the protein get to the lysosome to carry out its function.

Chaperone therapy for Fabry disease

The concept of using chaperone therapy for Fabry disease treatment dates back to 1995, when scientists discovered that a sugar molecule called galactose could stabilize the GLA enzyme in cell models.

Galactose was ultimately deemed impractical for people with Fabry due to the very high dosages needed for an effect to be observed. However, other small molecules similar to galactose were identified that could increase the enzyme’s activity with greater potency.

By harnessing the molecular properties of chaperone molecules, these pharmacological chaperones can be used to correct the misfolding or instability of the GLA enzyme, thereby preventing its degradation and allowing more enzyme to reach the lysosomes.

This approach, however, requires the production of an abnormal enzyme to begin with, so patients whose Fabry-causing mutations result in no enzyme being produced at all will not benefit from chaperone therapy.

Only misfolding mutations, or mutations resulting in a functional but misfolded and unstable GLA, can be targeted by chaperone therapy.

Galafold chaperone therapy

Currently, Galafold (migalastat) is the only chaperone therapy that is widely approved for Fabry disease. It is taken as oral capsules every other day.

Developed by Amicus Therapeutics, the medication is approved in the U.S. for adults with a confirmed diagnosis of Fabry disease and a mutation amenable to chaperone treatment. An estimated 35% to 50% of Fabry patients carry an eligible mutation; a full list is available in the therapy’s prescribing information.

In the European Union, Galafold is approved for Fabry patients 12 and older with eligible mutations. The therapy is also approved in many other countries worldwide.

Clinical trials, as well as data from real-world observational studies, have demonstrated that treatment with Galafold can help to reduce Gb3 accumulation in people with Fabry disease caused by eligible mutations, stabilizing kidney function and improving markers of heart health. The therapy has also been reported to help with pain management and to reduce gastrointestinal symptoms among eligible patients.

It’s recommended that patients taking Galafold undergo regular monitoring to ensure the therapy is working as expected and to deal with any complications that arise.

Potential side effects or complications from chaperone therapy

Galafold, the only approved chaperone therapy for Fabry, has been deemed generally safe and well tolerated in clinical trials and observational studies, resulting in few treatment-related side effects.

The most common side effects associated with the chaperone therapy in clinical trials were:

• headache
• the common cold (nasopharyngitis)
• urinary tract infection
• nausea
• fever.

Because Galafold is mainly excreted by the kidneys, people with severe kidney problems may be exposed to much higher levels of the drug than expected. The therapy is thus not recommended for patients with severe kidney problems or with end-stage kidney disease needing dialysis.

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