Dr Ailsa McGregor is a Senior Lecturer in the University of Otago School of Pharmacy, and one of the most recent additions to the Brain Health Research Centre. As the first speaker at the 2016 BHRC Conference she discussed her work on trying to determine whether the anti-smoking drug varenicline could help people with Huntington's disease.
Huntington's disease is a progressive neurodegenerative disease which causes motor dysfunction, cognitive decline, and eventually leads to death. There is currently no cure. The disease is caused by excessive repetition of a section of the huntingtin gene (HTT). When the length of this repeated section reaches a certain threshold, it produces an altered form of huntingtin protein. This mutant protein is thought to underlie the pathological changes observed in the HD brain and cause disease symptoms.
Brain cells communicate with one another via chemical messengers (neurotransmitters) that bind to specific sites (receptors). Analysis of the HD brain has shown a dramatic reduction in the neurotransmitter acetylcholine but no change in the number of a certain type of receptor for this neurotransmitter. These receptors play a key role in controlling movement and cognitive processes, like learning and memory. It is possible therefore that HD symptoms may result from under-activation of these receptors and that finding a replacement may provide some benefit.
Developing new drugs, testing them, and getting them through clinical trials can take decades. Dr McGregor decided to try and shorten this process by focusing on what was already available. She set out to find a drug which was already in clinical use for other illnesses, which could be used to stimulate those nicotinic receptors in people with HD.
Varenicline, also known as Champix®, is a drug prescribed by doctors to help people quit smoking. What interested Dr McGregor was that varenicline activated the alpha-4-beta-2 and alpha-7 nicotinic receptor subtypes which are found in brain regions most affected by HD.
In order to see whether varenicline had any effect on the disease Dr McGregor gave the drug to mice with a simulation of Huntington's disease. The mouse model of Huntington's disease was comparable to late-stage human HD, so any improvement varenicline made would be hard won. Dr McGregor's team tested the movement and cognition of the mice, in addition to testing for symptoms of depression and anxiety before and after treatment with varenicline. They consistently found significant improvements in motor function and memory in HD mice following treatment. They also saw reduced anxiety and depressive-like behaviour. The improvements could also be produced at lower doses of varenicline and lasted for many weeks after treatment.
It was a promising start, and so with this information Dr McGregor started a small study using human participants. The open label study was conducted to determine whether varenicline could be tolerated by people with HD, or whether there would be previously unknown side-effects which would negatively impact this at-risk group. No clinically significant side effects were found and after four weeks of treatment participants who completed the trial showed improvements in their movement, mood, and cognitive ability. It seemed to work.
At this stage Dr McGregor and her team are half way through a larger-scale clinical trial for varenicline in HD. They hope to have the results of this study by the end of 2016, and with any luck their work could provide some hope for patients living with HD.
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