The effectiveness of ambroxol — a molecule that improves the folding and maturation of abnormal glucocerebrosidase — does not depend only on the type of GBA mutation a Gaucher patient has, a study found.
Using primary cells from patients — particularly their blood cells or macrophages — could help determine the treatment’s efficacy beforehand, and improve personalized approaches.
While enzyme replacement and substrate reduction therapies successfully treat the systemic manifestations of Gaucher disease, none of these approaches is effective at treating patients with the neuronopathic form of Gaucher disease.
Researchers believe that the future of Gaucher treatments might lie in small molecules — called chaperones — that bind the mutated glucocerebrosidase and help it fold properly. These molecules can cross the blood-brain barrier and treat Gaucher manifestations in the central nervous system; however, their activity largely depends on the kind of GBA mutation a patient has.
Also, given that each patient has a unique genetic background, even patients with similar mutations might respond differently to these therapies. “In some patients, certain drugs do not work as expected; in others, treatment can have toxic effects,” researchers said.
Researchers at Lysosomal and Rare Disorders Research and Treatment Center in Vancouver now examined the effects of one of these chaperone molecules — called ambroxol — on cells collected from skin biopsies of Gaucher patients. These patients had type 3 disease, the neuronopathic form, and only 3-6% of the normal glucocerebrosidase activity.
Treatment with ambroxol increased glucocerebrosidase activity in control cells, suggesting that it does induce protein folding and its movement into the lysosome, where glucocerebrosidase exerts its function.
However, not all cells with the L444P/L444P mutation — the most common mutation leading to Gaucher disease type 3 — had an increase in glucocerebrosidase activity, suggesting that “chaperone activity of ambroxol could be modified by diverse factors and not only by the individual’s genetic variants,” researchers stated.
Investigators then explored which cells could be used to determine whether a patient would benefit from ambroxol. They found that certain cells from the blood — called peripheral blood mononuclear cells (PBMCs) — could lead to an expedited screening that took only five days.
Macrophages — a kind of immune cell that is particularly affected in Gaucher patients — could also be used to monitor ambroxol’s efficacy, researchers found. These cells would not only allow for measures of glucocerebrosidase activity, but also help monitor changes in immune pathways after treatment.
“Therefore, PBMCs and macrophages are the most relevant cell type to screen efficacy, toxicity, and inflammatory response in [Gaucher disease],” investigators said.
“Enzyme enhancement or chaperone therapy is a promising approach for the treatment of GD, especially when the [central nervous system] is involved. Ambroxol demonstrated good tolerability while enhancing GCase activity and improving neurological manifestations.”