A team led by New Zealand scientists think they've found a vital clue to developing the first treatment for Huntington's Disease.
The debilitating neurological disorder can lead to extensive loss of control over bodily movement, dementia and psychological disturbance and eventually premature death.
It directly affects one every 10,000 people and there is no treatment for it.
Now, international researchers led Professor Russell Snell and Dr Renee Handley, of the University of Auckland's School of Biological Sciences and Centre for Brain Research, have pinpointed one of the very earliest changes in the brain that results in the disease.
Their work, just published in prestigious scientific journal Proceedings of the National Academy of Sciences, identified elevated levels of the chemical urea in the brain of a transgenic sheep model, which matches those of human brains affected by Huntington's.
Because it is known that neurons are lost in the brain before any symptoms of Huntington's show, the long-term research focus of the group has been to determine the first biochemical change caused by the gene that leads to the cell death.
Results from the five-year study show that the Huntington's sheep model, which is symptom-free but carries the mutant form of the human huntingtin gene, have the same increase in urea in the brain as the post-mortem brains of people who have died of Huntington's.
Urea is a naturally occurring chemical in the body, produced from ammonia. Both are normally excreted as they are toxic to cells.
"Genetic disorders of the urea system result in increased levels of ammonia and urea, causing severe neurological symptoms," Handley said.
The findings clearly pointed to brain urea, or ammonia, as a therapeutic target for Huntington's disease.
"What gives us hope is that treatments already exist for reducing urea and ammonia in the brain.
"These could very simply be tested in Huntington's disease, initially using our sheep model."
Snell was part of the international team that identified the gene mutation that causes Huntington's in 1993.
"The next step, which we have already begun, is testing how we might treat Huntington's disease with this knowledge.
"It is a terrible disorder, devastating for families and our focus is on discovering a therapy as quickly as possible."
Meanwhile, the first drug targeting the cause of Huntington's disease was found to be safe and well-tolerated in its first human trial.
University College London (UCL) scientists have been monitoring a human clinical trial of a drug that successfully lowered the level of the harmful huntingtin protein in the nervous system.
After more than a decade in pre-clinical development, this first human trial of huntingtin-lowering drug began in late 2015, with sponsorship by Ionis Pharmaceuticals.
The trial involved enrolling 46 patients with early Huntington's disease at nine study centres in the UK, Germany and Canada.
Each patient received four doses of either IONIS-HTTRx or a placebo, given by injection into the spinal fluid to enable it to reach the brain.
As the phase trial progressed, the dose of IONIS-HTTRx was increased several times, according to the ascending-dose trial design.
"The results of this trial are of ground-breaking importance for Huntington's disease patients and families," said Professor Sarah Tabrizi, director of University College London's Huntington's Disease Centre.
"For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well-tolerated.
"The key now is to move quickly to a larger trial to test whether the drug slows disease progression."