Chaperone Therapy for Pompe Disease

People with Pompe disease have a defective acid alpha-glucosidase (GAA) enzyme caused by a mutation in the GAA gene.

Chaperone therapy for Pompe disease is currently in the clinical trial stage and aims to restore function to the defective GAA enzyme. Chaperone therapy is also being investigated in other lysosomal storage disorders, such as Gaucher disease and Fabry disease.

How chaperone therapy works

For an enzyme to work, it must fold properly. Genetic mutations can destabilize an enzyme, causing it to unfold or misfold. This affects the enzyme’s ability to move to its correct location in the cell, interfering with its overall function. Chaperones are proteins that exist naturally in the cell that ensure that enzymes fold correctly.

Chaperone therapy for Pompe disease

In Pompe disease, chaperone therapy uses small molecules that bind to the dysfunctional GAA enzyme, helping it to fold correctly and ensuring that normal enzyme activity is restored. Chaperone therapy may help overcome the limitations of enzyme replacement therapy (ERT), the current standard of care for Pompe disease. Current ERT for Pompe disease does not adequately resolve skeletal muscle disease.

Proof-of-concept studies testing chaperone therapy for Pompe disease discovered that a pharmacological chaperone called derivative N-(n-butyl) deoxynojinimycin (NB-DNJ) was able to increase the levels of GAA enzyme in cultured cells from patients who had Pompe disease.

Other studies in cultured cells from Pompe patients and in mouse models of the disease found that NB-DNJ was able to enhance the effectiveness of ERT.

Amicus Therapeutics is currently developing a combined pharmacological chaperone/ERT therapy for Pompe disease, called ATB200/AT2221, using its trademarked CHART (chaperone-advanced replacement therapy) technology. This compound is currently in a Phase 1/2 clinical trial (NCT02675465), and Amicus recently announced positive results from the trial.

Limitations of chaperone therapy

Although all patients with Pompe disease have a defective GAA gene, there are many different variants of the GAA gene mutation that have been documented. Not all of these mutations may respond to chaperone therapy. Chaperone therapy alone may not be enough to reverse enzyme defects, although this is also a challenge with ERT.


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