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Small Molecule Therapy for Gaucher Disease and GBA1-Associated Parkinson’s Disease

Mutations of the GBA gene cause Gaucher disease and are a risk factor for Parkinson’s disease. A new type of therapy using small molecule chaperones can potentially treat both conditions.

Gaucher disease is a genetic disorder in which low levels of the enzyme glucocerebrosidase (GCase) allow the buildup of fatty chemicals called glucocerebrosides. The excess glucocerebrosides cause damage by accumulating in several tissues, including the liver, bone marrow, and spleen. In cases of severe mutations, there are serious neurological problems and brain damage.

What Are Small Molecule Chaperones?

Small molecule chaperones are molecules that bind to enzymes. Enzymes are protein molecules that assist many chemical reactions in your body, and they must maintain their conformation to work correctly. Small molecule chaperones help enzymes to preserve their proper conformations.

In people with Gaucher disease, the chaperone stays bound to the enzyme as it moves into the lysosome, a part of the cell where glucocerebrosides build up. “Once inside the lysosome, the chaperone may detach from the enzyme. Then the enzyme is free to break down glucocerebrosides,” says Dr. Ricardo A. Feldman, Ph.D., a professor in the Department of Microbiology and Immunology at the University of Maryland School of Medicine. His lab is currently researching small molecule therapy and developing cellular models for studying Gaucher disease and GBA1-associated Parkinson’s disease.

How Does Small Molecule Therapy Work?

Small molecule chaperones can increase overall GCase enzyme activity by protecting mutant GCase from degrading. This allows it to reach the lysosome so it can do its job. People who are carriers of Gaucher disease make 50% of the normal GCase enzyme, and chaperones may enhance the activity of both normal and mutant GCase. Restoring GCase activity reduces Gaucher symptoms over time.

Potential for Small Molecule Chaperones to Treat Gaucher Disease

Small molecule therapy, given orally or by IV, may be a helpful addition to Gaucher treatments. Where traditional enzyme replacement therapy (ERT) provides your body with normal GCase, small molecule therapy increases the activity of mutant GCase already in your body.

However, small molecule therapy is unlikely to replace established treatments such as ERT and substrate reduction therapy (SRT). “ERT is still the gold standard for treating Gaucher disease at this time,” Dr. Feldman says.

He also cautions that chaperones don’t work equally well for every genetic mutation that leads to Gaucher disease. And, even for two people with the same Gaucher mutations, small molecule therapy may not be equally effective. This difference is due to other factors such as:

  • Age
  • Environment
  • Each person’s unique genetic makeup

Dr. Feldman details the potential of small molecule therapy for each type of Gaucher disease:

Small molecule therapy for Gaucher disease type 1

Small molecule therapy may be most helpful for people with Gaucher disease type 1, which is the mildest form. “This treatment could be used together with enzyme replacement and other therapies,” Dr. Feldman says.

Small molecule therapy for Gaucher disease types 2 and 3

Small molecule chaperones may be less helpful for people with more severe forms of Gaucher disease.

“There are some reports with small groups of patients that treatment with the chaperone Ambroxol can improve neurological problems in type 3 Gaucher disease. But it may only help before major organ damage has occurred,” Dr. Feldman says. “The key to all of these treatments, especially with type 2 and type 3 Gaucher disease, is to start very early.”

Small Molecule Therapy for GBA1-Associated Parkinson’s Disease

About 7% of people with Parkinson’s disease have GBA1 gene mutations (also called GBA1-associated Parkinson’s disease). Parkinson’s disease is a condition that affects parts of the brain and worsens over time.

People with Gaucher disease and carriers of this disorder have an increased risk of developing Parkinson’s disease, but only a small percentage of these individuals will develop this disorder. According to Dr. Feldman, if individuals at the highest risk of developing Parkinson’s could be identified early, starting small molecule therapy before problems arise may one day slow the progression of GBA1-associated Parkinson’s.

Research is underway to develop tests that identify people with GBA1 mutations at high risk of developing Parkinson’s. Identifying these people before symptoms begin is key to effective treatment with small molecule chaperones and/or other therapies.

Safety of Small Molecule Therapy

Little information is available about the side effects of small molecule chaperones, and researchers still need to perform long-term safety trials.

“Small molecules may interact with unintended targets in addition to the intended targets, which could lead to side effects,” Dr. Feldman says. “High doses of these molecules need to be studied carefully to ensure any potential side effects are acceptable. As with any treatment, side effects may vary from person to person.”

Ongoing Clinical Trials

No small molecule chaperones are currently approved for Gaucher disease treatment in the United States. However, clinical trials in other countries are underway.

Researchers in a number of countries are investigating Ambroxol for Gaucher disease treatment. Ambroxol is a small molecule chaperone available in other countries as a cough medicine. At much higher doses, it may improve symptoms in people with type 3 Gaucher disease. Ambroxol can cross the blood-brain barrier, so it may help with neurological symptoms.

One biotech company has used computer-assisted design to develop a small molecule chaperone that is now undergoing safety clinical trials in Australia.

The results of clinical trials carried out in other countries may be submitted to the U.S. Food and Drug Administration (FDA) for consideration. If trials show that small molecule chaperones are safe and effective treatments, the FDA may approve them for use in the U.S.

How the National Gaucher Foundation Can Help

If you or a loved one lives with Gaucher disease, the National Gaucher Foundation is here for your family. We offer resources to optimize your health with Gaucher disease and connect you with the support you need.

 

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