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Headlines 13 The antibody therapy works by targeting the NMDA receptors found in neurons. These receptors play an important role in learning, memory, and neuroplasticity, and can become dysfunctional when there is an excess of glutamate in the brain – an amino acid that travels along synapses relaying messages between neurons. Too much glutamate causes the nerve cells to become overexcited and fire at the wrong times. In HD, the fine balance between glutamate acting at NMDA receptors is disrupted, resulting in brain cell damage or cell death. This is also seen in a range of other neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases 1 . “The idea of targeting the NMDA receptor with antibodies was conceived way back in 2000 when I was working as a postdoc,” says Dr Young, who completed her PhD in neuropharmacology under the supervision of Professor Mike Dragunow. “We showed this therapy – generated using a genetic vaccine – was effective in limiting neuronal cell loss in models of stroke and temporal epilepsy. The project has been brewing on and off for a while, but I started looking at it more in depth in the last several years. This is the first time it has been tested in HD.” The therapy has already been shown to improve cognitive function and resilience of the brain when delivered intravenously in mouse models. “The primary goal of the new research is to test the therapy in mouse models. A series of cognitive and motor learning tests will then be run to see if the treatment leads to improved learning and memory. If the treatment works, we expect to see that the mouse models either don’t develop, or develop fewer, deficits or neuropathology than those that receive a placebo treatment,” says Dr Young. “Our current theory is that our therapy works primarily by getting into the brain to act on NMDA receptors which are most abundant in the brain. However, the NMDA receptor is also found in lower amounts on cells such as platelets that are involved in blood clotting, beta cells in the pancreas, and endothelial cells that line blood vessels.” Investigating the therapy’s impact on these other cell types will also help address any questions raised about possible untoward effects, says Dr Young. “Pharmaceutical companies have put a lot of effort into developing medicines that target the NMDA receptor. The bar has been raised, meaning we have to generate a very strong set of convincing data showing it works without any adverse effects. Pieces of our data all fit together in the right place, but to get it to the clinic, we’re going to pick it apart piece by piece and probe it from many angles so we have a really strong understanding of how our therapy works. “For a therapy suitable for use in humans, we’ll need to refine our approach to make a monoclonal antibody therapy. This means it will target one spot on the NMDA receptor, so we can better predict how it will work. Human clinical trials could be around six to 10 years away,” she says. “Ultimately, the treatment might be useful for other brain diseases associated with impaired memory function like mild cognitive impairment or Alzheimer’s disease – or even just preventing the normal cognitive decline that occurs with ageing.” Dr Young says she’s really excited about this therapy, and she is acutely aware of what’s at stake. “I don’t personally know the Hanly family but I know their story. I attended a Centre for Brain Research dinner a few years ago where I was seated with one of the young Hanly whānau, Micheal, who spoke to the audience about his journey,” she says. “I always think back to this, and the human face of the disease, when the going gets tough in the lab. It definitely motivates me to keep pushing the boundaries and driving our research forward – so we can help people like Micheal.” HD facts: • In 1872, American physician George Huntington reported seeing patients who looked intoxicated walking along the street. This was the original description of Huntington’s Chorea (chorea is from the Greek word for dance). • The Huntingtin gene – the gene for Huntington’s disease – was discovered in 1993. • Around 150 of the 700 brains in The Neurological Foundation Human Brain Bank are from cases of HD. • Medication can help improve the movement and psychiatric symptoms, and therapies such as speech, physical, occupational and psychotherapy may improve quality of life, but there is currently no cure. For support, go to hdauckland.org A very moving documentary on YouTube made by Pat Hanly’s granddaughter, Lillian, shows the choices faced by someone with HD in their family. https://www.youtube.com/ watch?v=ihXH0_nAVag “Ultimately, the treatment might be useful for other brain diseases associated with impaired memory function...” 1 https://my.clevelandclinic.org/health/articles/22839-glutamate