A recent article in CheckOrphan describes a study that was conducted by Researchers at the Lysosomal and Rare Disorders Research and Treatment Center in Vancouver, B.C. The study examines the effects of ambroxol on Gaucher type 3 patients.
The title of the study is “Individualized screening for chaperone activity in Gaucher disease using multiple patient-derived primary cell lines.”
See American Journal of Translational Research for study details.
About Gaucher (“GO-SHAY”). disease
Gaucher disease (GD) is a genetic disorder caused by a hereditary deficiency of the enzyme glucocerebrosidase which is needed to break down the chemical glucocerebroside.
This enzyme defect causes an accumulation of glucocerebroside in white blood cells. The event also occurs in macrophages, which is a type of white blood cell that ingests foreign material. Macrophages play a major role in the immune response.
The accumulation can occur in the liver, spleen, kidneys, lungs, brain, and bone marrow. Some of the symptoms are fatigue, anemia, bruising, and low platelet count, primarily occurring outside the central nervous system.
Other symptoms may include the enlargement of the liver and spleen, liver malfunction, painful bone lesions, skeletal disorders, swelling of lymph nodes and neurological complications. There is also the risk of infection.
Rarely, the brain may be affected. This causes abnormal eye movements, difficulties in swallowing, rigid muscles and seizures.
In general, the range of symptoms varies widely. However, some people who have been diagnosed with Gaucher’s disease do not experience any symptoms.
Causes of Gaucher Disease
There are three main types of Gaucher disease. All three types are inherited and both parents must be carriers. That presents a 25% chance a child will be affected. It is recommended that each child receives genetic testing if family members are known to be carriers.
There are about 80 mutations. The three main types are:
- Type I, the most common, displays no neurological symptoms
- Type II affecting small children has a poor prognosis and short life span
- Type III is a mildly acuteneurological form of Gaucher disease. The life span associated with this type of disease is about 30 years.
To date, there have been two effective treatments for Gaucher’s disease, namely substrate reduction therapy and enzyme replacement therapy. However, neither of these approved therapies penetrate the blood-brain-barrier to enter the central nervous system. These treatments have not been effective in the type of Gaucher disease known as “neuronopathic.”
Researchers now believe that the success of Gaucher treatments may be found in a type of molecule called chaperones. These molecules are a protein that shapes other protein molecules to allow them to work as receptors or be secreted from cells. The chaperones allow the mutated glucocerebrosidase protein to fold normally.
The chaperone molecules can cross the blood-brain barrier and treat Gaucher manifestations in the central nervous system. Their activity, however, depends on the patient’s GBA mutation.
Cells collected from skin biopsies of three Gaucher patients were examined by the Vancouver researchers for the effects of ambroxol, a chaperone molecule.
Each of the three patients had the form of type 3 Gaucher disease that occurs as a result of neuron degeneration (neuronopathic) with between three to six percent of the normal glucocerebrosidase activity.
The study revealed that ambroxol’s effectiveness does not depend solely upon the type of GBA mutation the patient has. The use of primary cells, especially the patient’s blood cells or macrophages, may predetermine the efficacy of the treatment as well as improve personalized approaches.
Ambroxol has been shown to improve the folding and maturation of abnormal glucocerebrosidase. Folding is a process whereby the protein structure acquires its functional shape.
Also, since every patient has a distinct genetic makeup, even patients with comparable mutations could respond differently to these approaches.
“In some patients, certain drugs do not work very well; in others, treatment can have toxic effects,” researchers said.
Glucocerebrosidase activity was increased in the control cells after treatment with ambroxol. This suggests that ambroxol does induce protein folding and its movement into the lysosome which is where glucocerebrosidase exerts its function.