Research on the medication Ambroxol and other existing drugs with the potential to be repurposed offer hope for improving the lives of people with Gaucher disease.

Marco Toffoli, MD, PhD, is the principal investigator of a new clinical trial for Ambroxol. He is a neurologist and researcher at UCL Queen Square Institute of Neurology and a consultant for the U.K. National Health Service.

Dr. Toffoli’s research focuses on the GBA gene. Mutations in this gene cause Gaucher disease and are risk factors for Parkinson’s disease. Gaucher disease is a rare genetic disease caused by a deficiency in the enzyme glucocerebrosidase (GCase). Early research suggests Ambroxol may boost the activity of GCase, and this potential treatment could fill a gap in current therapies.

The GBA Gene and GCase in Gaucher Disease

The GBA gene produces the GCase enzyme, which breaks down a compound called glucocerebroside. GCase performs this function in an area of cells called the lysosome. The lysosome is a compartment where enzymes like GCase break down waste molecules so your body can eliminate them. “This is like the meatgrinder of the cells, breaking down everything that’s unwanted,” says Dr. Toffoli.

With Gaucher disease, a mutation in both  GBA genes lead to mutant GCase that easily becomes misfolded, which affects its function. Healthy GCase enzyme effectively breaks down glucocerebroside, but mutant GCase enzyme can’t perform this function properly. “When GCase isn’t working, there’s an accumulation of glucocerebroside,” says Dr. Toffoli. “This leads to an imbalance in some proteins and fats inside the cells, which causes a variety of problems and symptoms.”

Limitations of Current Gaucher Disease Treatments

Current treatments for Gaucher disease can effectively manage and prevent some symptoms, especially in type 1, the less severe form of the disease. The accepted treatments for Gaucher disease are:

• Enzyme replacement therapy (ERT): ERT provides GCase enzyme to help raise the level of properly functioning enzyme in the body.
• Substrate reduction therapy (SRT): SRT drugs partially block the production of glucocerebroside.

However, these treatments have little effect on Gaucher disease types 2 and 3. “ERT and SRT treatments are great for systemic symptoms,” says Dr. Toffoli. “The downside of both these treatments is that they don’t cross the blood-brain barrier and because the mechanism of brain damage in Gaucher types 2 and 3 might be different from that of systemic symptoms.” The blood-brain barrier prevents many drugs and other substances from reaching the central nervous system, which includes the brain. Due to these limitations, ERT and SRT do not help with some of the most serious Gaucher disease symptoms.

“We can divide the symptoms of Gaucher disease into two categories, systemic and neurological,” says Dr. Toffoli. “People with type 1 Gaucher disease only get systemic symptoms, while people with types 2 and 3 also get neurological symptoms.” Researchers observe that the poorer GCase functions, the greater the severity of Gaucher disease symptoms.

Systemic Gaucher disease symptoms include:

• Bone pain and other bone symptoms
• Blood disorders
• Enlarged liver and spleen
• Fatigue
• Memory loss
• Numbness and pain in the hands and feet

Neurological Gaucher disease symptoms include:

• Brain damage
• Cognitive problems
• Muscle and movement disorders
• Seizures

Researchers are looking for treatments to increase GCase activity in the central nervous system. A treatment that crosses the blood-brain barrier to preserve GCase activity in the brain could prevent and possibly reverse neurological symptoms. Ambroxol is an existing medication researchers are investigating for its potential to activate GCase in the brain.

What Is Ambroxol?

“Ambroxol is an old drug,” says Dr. Toffoli. “The plant it comes from has been known to some populations in India for two thousand years.” The plant Ambroxol derives from, Adhatoda Vasica, was traditionally used in cough remedies. Ambroxol is an expectorant that helps loosen mucous in the lungs. Ambroxol is available in many countries as a cough medicine. However, it is not available in the U.S.

“Ambroxol is one compound in a class of molecules that increase GCase activity through a process called chaperoning,” says Dr. Toffoli. These chaperone molecules, used in small molecule therapy treatments, work by preserving GCase enzyme so it can enter the lysosome and function properly. The chaperone molecule binds to the enzyme and adjusts its folding to hold the correct shape and reach the lysosome intact.

Dr. Toffoli is working on AsPRO-PD, a trial of Ambroxol for Parkinson’s disease treatment. The results of this trial directly apply to GCase in Gaucher disease.

Promising Early Results

At high doses — much higher than cough medicine doses — Ambroxol crosses the blood-brain barrier and acts as a chaperone for GCase. “In a Phase 2 trial of 20 people, we showed that Ambroxol reached the central nervous system and engaged with the target GCase,” says Dr. Toffoli.

Dr. Toffoli notes that the main downside of Ambroxol is the high dose required to affect GCase. He also cautions that although the Phase 2 results are very promising, more research is necessary to prove that Ambroxol prevents or reduces Parkinson’s and Gaucher disease symptoms. AsPRO-PD, a Phase 3 trial with over 300 participants is underway to investigate Ambroxol’s potential as a treatment.

Researchers are also collecting data from people living with Gaucher disease who decide to take Ambroxol on their own. In rare cases, providers prescribe high doses of Ambroxol off-label for patients with severe symptoms that are not alleviated with ERT or SRT. Off-label use of a drug means that it has yet to pass clinical trials proving its effectiveness or safety.

Ongoing Ambroxol Research

Dr. Toffoli is very hopeful about the potential of Ambroxol but acknowledges that the Phase 3 trial may show that Ambroxol is ineffective. “That’s why we must perform the trial to find out,” he says.

In addition to possibly improving neurological symptoms, Ambroxol may also prevent Parkinson’s disease in people with the GBA mutation for Gaucher disease. This potential breakthrough is significant because people with GBA mutations have a much higher chance of developing Parkinson’s disease, and worldwide, Parkinson’s disease affects millions of people.

Because Parkinson’s disease affects so many people, there is substantial funding to search for a treatment or cure. Parkinson’s disease researchers are continuously identifying compounds that may be effective GCase chaperones. Successful trials of these molecules would also benefit people with Gaucher disease because of the connection between these two conditions.

Hope for the Future

The Phase 3 Ambroxol trial, which has four years remaining, is the most advanced trial for a drug of its kind. “We have hope, for sure,” Dr. Toffoli says. “GBA is one of the genes we know best out of the entire human genome. The research is well-funded, and there’s a huge amount of research on GBA at the moment.”

Dr. Toffoli encourages people with Gaucher disease to participate in studies. “Your contribution to the research is very valuable, whether you take a survey or take part in a trial,” he says. “There is a positive outlook for the future, but we’re not quite there yet.”

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.

SOURCES

• National Gaucher Foundation — Understanding the Neurological Symptoms of Gaucher Disease https://www.gaucherdisease.org/blog/neurological-symptoms-of-gaucher-disease/
• Science Direct — Ambroxol Chapters and Articles https://www.sciencedirect.com/topics/neuroscience/ambroxol