Cleaning up with Ambroxol

Exciting news recently with the announcement of the Ambroxol study starting.

Exciting for two reasons:

1. Ambroxol has the potential to make a major impact in the lives of some people with Parkinson’s disease.
2. It illustrates how FAST things are moving in the world of Parkinson’s disease!

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Inside each and every cell, there are millions of tiny actions taking place. Minute processes all working in a collective manner allowing the cell to function normally. There are lots of proteins helping to make other proteins, lots of proteins helping other proteins to get to where they need to be, and lots of proteins helping to break down other proteins after they have done their job.

All this activity generates a lot of waste. And a fundamental part of the activity in any cell is waste disposal. If that does not function properly, the cell is in serious trouble.

One of the most common genetic mutations associated with Parkinson’s disease – called GBA – results in cells having trouble getting rid of waste.

Adapted from a cartoon by Dr Jing Pu. Source: The Nichd connection

What is GBA?

Glucocerebrosidase (or GBA) is an enzyme that helps with the recycling of waste. It is active in inside ‘lysosomes‘.

What are Lysosomes?

Lysosomes are small structures inside cells that act like recycling centers. Waste gets put inside the lysosome where enzymes like GBA help to break it down into useful parts. Mutations in the GBA gene can result in an abnormally short, non-functioning version of the enzyme. And in those cases the breaking down of waste inside the lysosome because inhibited.

What is the connection between GBA and Parkinson’s disease?

GBA mutations are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene are at higher risk of developing Parkinson’s disease than the general population. And people with Parkinson’s are approximately five times more likely to carry a GBA mutation than healthy control subjects.

So what is Ambroxol?

Ambroxol is a commonly used treatment for respiratory diseases. It promotes mucus clearance and eases coughing. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ok, but why the excitement for Parkinson’s disease?

In May of 2014 – less than 2 years ago – this study was published:

Title: Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells.
Authors: McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH.
Journal: Brain. 2014 May;137(Pt 5):1481-95.
PMID: 24574503    (This report is OPEN ACCESS if you want to read it)

It was the first time that Ambroxol – a commercially available drug – had been tested in a Parkinson’s disease related context.

In this study the researchers collected skin cells (called fibroblasts) from eleven people with GBA mutations (some had been diagnosed with Parkinson’s disease). They measured the amount of glucocerebrosidase protein and enzyme activity in these cells, and they found that glucocerebrosidase enzyme activity was significantly reduced in fibroblasts from GBA mutations (on average just the enzyme was acting at just 5% of normal levels). They found that ambroxol increased glucosylceramidase activity in fibroblasts from people with GBA mutations AND in fibroblasts from healthy controls. Ambroxol treatment also reduced markers of oxidative stress in GBA mutant cells.

Given the increase in glucocerebrosidase activity after ambroxol treatment, the researchers wondered whether the drug would reduce alpha-synuclein levels in cells that were over-expressing this protein. Amazingly, after 5 days of ambroxol treatment, levels of alpha-synuclein had decreased significantly (15% on average 15%).

You can understand why the researchers were a little bit excited by these results. Here was a drug that re-activated the recycling unit in the cell and reduced levels of one of the main proteins associated with Parkinson’s disease. If the drug can reduce the levels of alpha synuclein in the brains of people with Parkinson’s disease, maybe the researchers will be able to slow down (or even halt) the disease!

Additional studies have now been reported which have confirmed the initial results.

And now the clinical trial?

Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), it was announced this week that they had started recruiting subjects to be involved in a clinical trial at the Royal Free Hospital in London. The trial is a phase 1 study which will test the safety of Ambroxol in Parkinson’s disease. The researchers will also look to see if Ambroxol can increase levels of glucocerebrosidase and whether this has any beneficial effects in the subjects. The study will be conducted on 20 people with Parkinson’s disease who also have GBA mutations. They will be given the drug and followed over the next 24 months.

These are exciting times for the world of Parkinson’s disease as these drugs are no longer simply reducing the motor features of the condition, but actually attempting to slow/halt the disease.

And as we suggested at the start of the post the pace of these developments is becoming hard to keep up with.