Chaperone therapy is a treatment strategy for Gaucher disease.

How chaperone therapy works

Gaucher disease is caused by mutations in the gene encoding for glucocerebrosidase, an enzyme that normally breaks down, or metabolizes, a fat molecule called glucocerebroside into simple sugar (glucose) and a simple fat molecule (ceramide). Mutations in this gene result in the enzyme being unstable because it cannot fold properly. It is then targeted for degradation by the quality control mechanism of cells. This results in the accumulation of glucocerebroside to toxic levels inside cells, and leads to the symptoms of Gaucher disease, including enlarged liver and spleen (hepatosplenomegaly), low counts of red blood cells (anemia) and platelets (thrombocytopenia), fragile bones, and neurological problems (neuropathy).

The strategy of chaperone therapy is to use small molecule compounds that can specifically bind to faulty glucocerebrosidase and help it fold properly. When correctly folded, the enzyme can escape degradation and get transported to the lysosomes where it binds to its natural substrate, glucocerebroside, and metabolizes it. The therapy’s goal is to decrease glucocerebroside levels and alleviate the symptoms of Gaucher disease.

The advantage of chaperone therapy over enzyme replacement therapy — the primary treatment strategy, in which recombinant glucocerebrosidase enzyme is infused into the patient — is that these small molecules can cross the blood-brain barrier. That means chaperone therapy can be used for treating both non-neuropathic and neuropathic types of Gaucher disease.

Chaperone therapy candidates for Gaucher disease

Several small molecules, summarized below, have been studied for their potential as chaperones in Gaucher disease.

Zavesca (miglustat)

Zavesca is approved by the U.S. Food and Drug Administration as a substrate replacement therapy for type 1 Gaucher disease patients. Miglustat is a molecule similar to glucose, which is one of the products of glucocerebroside metabolism. It binds to the substrate binding site of glucocerebrosidase (the active site where glucocerebroside normally binds) and improves its stability, cellular concentration, and transport to the lysosome.

Ambroxol hydrochloride

Ambroxol hydrochloride is a commercially available cough and cold medicine, commonly used as an expectorant. It has been shown to increase glucocerebrosidase activity in the brains of mice and cynomolgus monkeys. A pilot study in five neuropathic Gaucher disease patients showed that high-dose oral ambroxol hydrochloride was safe and well-tolerated, increased the activity of glucocerebrosidase in blood cells, permeated the blood-brain barrier, and improved neurological disabilities, including myoclonus (muscle jerks) and pupillary light reflex in the eye. A Phase 2 clinical trial (NCT03950050) is currently recruiting participants in Israel to test the efficacy of ambroxol in type 1 Gaucher disease.


Isofagomine (also called afegostat or AT2101) is the best studied among the experimental chaperone therapeutics. It has been tested by Amicus Therapeutics as a candidate for Gaucher disease. Isofagomine binds at the active site of glucocerebrosidase because it resembles glucose. Preclinical studies with cells isolated from Gaucher disease patients, and multiple mouse models (with different mutations in the glucocerebrosidase-encoding gene) have shown increased amounts and activity of glucocerebrosidase in the lysosomes. In one of the mouse models, isofagomine treatment increased glucocerebrosidase activity in the spleen, liver, lungs, and brain tissues, and reduced the characteristic pathology of Gaucher disease, hepatosplenomegaly. However, in Phase 2 clinical trials conducted in 18 Gaucher disease patients, only one showed a clinically meaningful response, and therefore the trial was stopped.

Bicyclic l-idonojirimycin

A study published in Chembiochem reported that bicyclic derivatives of l-idonojirimycin, another molecule that resembles glucose in structure, showed chaperone characteristics when used to treat cells isolated from patients with a specific mutation in the glucocerebrosidase-encoding gene that commonly causes neuropathic Gaucher disease.

NCGC758 and NCGC607

NCGC758 and NCGC607 are two small molecule candidates that emerged from a study that used a high throughput screen to find chaperone candidates that could improve the transport and activity of faulty glucocerebrosidase to the lysosome. A recent study showed that these two compounds increased the concentration and activity of the glucocerebrosidase.

Further studies and clinical trials are necessary to establish whether any of these candidate chaperone molecules can be effective treatments for Gaucher disease.


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