How bicyclic l-idonojirimycin derivatives work
Gaucher disease is caused by mutations in the GBA gene, which provides instructions to build an enzyme called beta-glucocerebrosidase (GCase). The role of GCase is to break down the fat molecule glucocerebroside.
GCase has to be folded in a specific way to function. Defective GCase cannot fold correctly, which affects its function to degrade glucocerebroside. This leads to the accumulation of the fat molecule inside cells. Chaperones such as bicyclic l-idonojirimycin derivatives bind to GCase and help it fold properly, thereby restoring its function.
Because they can cross the blood-brain barrier, bicyclic l-idonojirimycin derivatives are a potential treatment for non-neuropathic as well as neuropathic types of Gaucher disease.
Studies for bicyclic l-idonojirimycin derivatives
Bicyclic l-idonojirimycin derivatives have not been tested in clinical or preclinical studies.
One study assessed whether bicyclic l-idonojirimycin derivatives can enhance the function of GCase enzyme in kidney cell lines with N370S or L444P mutations. The N370S mutation is associated with type 1 Gaucher disease, a non-neuropathic form. The L444P mutation can cause neurological manifestations.
Three different bicyclic l-idonojirimycin derivatives were tested. In cells with the N370S mutation, the addition of a bicyclic l-idonojirimycin derivative to the cell medium increased GCase activity 2.5 to threefold. In cells with the L444P mutation, the increase was two to fivefold. These results demonstrate that bicyclic l-idonojirimycin derivatives can restore GCase activity.
To assess whether bicyclic l-idonojirimycin derivatives can increase GCase function inside the human body, animal studies must be performed before clinical trials begin.
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