Preventing the brain’s decline

A molecule that has proved effective in warding off Huntington’s disease in mice is set to go into a clinical trial, with hopes that it will eventually delay the onset of the devastating disease in people.

Professor Anthony Hannan and his collaborators have worked on NAC (N-acetylcysteine) in recent years demonstrating its benefits in a special mouse model of the human disease. Now, Anthony will watch with enormous interest as colleagues including clinicians elsewhere in Australia translate these Florey discoveries into long-term trials of NAC as a drug.

“Huntington’s is fatal and currently incurable – we desperately need new clinical trials to find an approach to prevent and treat it,” he says.

The neurodegenerative disease has three main sets of symptoms which typically appear around middle age; psychiatric (including depression), cognitive (culminating in dementia) and motor disorders in which movements become uncontrollable (including involuntary, twitching movements called chorea). Children with a parent with the mutation have a 50 per cent likelihood of inheriting the condition.

Anthony and colleagues, including Drs Dean Wright and Thibault Renoir from the Florey, found in separate studies that NAC fights Huntington’s on several fronts. Firstly, it acts as an anti-oxidant. Oxidation is a chemical reaction that can produce ‘free radicals’, which can cause damage to cells. In this case, NAC protects against the oxidative stress that damages the ’batteries’ or energy sources of cells (mitochondria). Preventing the brain’s decline Preventive medicine has to be the key to health in the 21st Century. Professor Anthony Hannan, head of the Epigenetics and Neural Plasticity laboratory.

Their study found that, in doing this, NAC was able to delay the onset of the disease.

“We’re targeting people who know they have the gene mutation for Huntington’s and will eventually get it, but who don’t have symptoms yet.”

In another mechanism, NAC appears to act on the way glutamate regulates communication within the brain. Glutamate excites brain cells, passing nerve signals from one brain cell on to the next, but too much of it can be toxic to the neurones receiving it. The researchers found that NAC countered ‘excitotoxicity’ in Huntington’s and helped with movement disorder and depression-like symptoms associated with the disease.

Moreover, related molecules may help patients with other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and motor neurone disease, Anthony says. Professor Ashley Bush, Dr Scott Ayton and others at the Florey are investigating related drugs in the context of treating dementia, their work intersecting with that of Anthony and his team.

Anthony, who has been working on Huntington’s disease for 20 years, says the forthcoming trial has another unique aspect; it will be conducted on people who have the gene mutation for Huntington’s but who are pre-symptomatic.

“Because NAC is FDA-approved, has been trialled for other disorders and is considered a safe drug and can be taken for a long time, there’s a capacity to give it to people who don’t yet have the disease, knowing the safety is excellent.

“We can generally predict when people will start to get symptoms from previous research and will be trying with this trial to test whether we can delay the onset of symptoms.”

If the ground-breaking approach is successful it could be applied to other neurodegenerative diseases, Anthony says.

“We know with our colleagues working on dementia at the Florey that a proportion of people diagnosed with mild cognitive impairment will go on to get Alzheimer’s disease. “The kind of brain imaging being done at the Florey together with genetics and other blood biomarkers for Alzheimer’s that have been developed here can all predict who will be most likely to progress to full-blown dementia – that’s analogous to looking at the gene mutation, and biomarkers, in people with Huntington’s.

“They’re looking at ultimately targeting people even before the stage of mild cognitive impairment.” Anthony says it’s vital that such approaches are taken.

“Preventive medicine has to be the key to health in the 21st Century,” he says. “If we don’t achieve that, every health system in the world may suffer the strain of an increasing burden of disease; ‘Band-aid medicine’ for people who are already sick is necessary but not sufficient in the long term. It’s just not a sustainable approach to optimising life-long health and ageing across our whole population in the decades ahead.”

Further funding is still being sought for the NAC trials, which are now in the design phase.