A novel drug for Huntington’s disease has delivered “groundbreaking” results in its first clinical trial, according to researchers at University College London. Both safe and well-tolerated, the drug successfully lowered the level of the injurious huntingtin protein across the nervous systems of 46 patients with the disease.

This is the first human trial of the drug, named IONIS-HTTRx, which had been in pre-clinical development for over ten years before the clinical trial started in late 2015. In the trial, each patient received four doses over as many months of either IONIS-HTTRx, or of a placebo. Both were given by injection into the spinal fluid, to enable the drug to reach the brain and to make sure that patients did not know that they were receiving a placebo, respectively. Further, as the trial progressed, the dose of the drug was increased several times, as per the ascending-dose trial design, to establish its therapeutic and toxic limits.

The major unknown was whether the trial would show that IONIS-HTTRx could lower the concentrations of the mutant huntingtin protein – believed to be responsible for the symptoms of the disease – in the central nervous system. Using an exquisitely sensitive assay developed by the team led by Professor Sarah Tabrizi, the levels of the protein were measured in each patient’s spinal fluid before and after treatment. Overall, comparisons of the drug against the control showed a statistically significant, dose-dependent lowering of the mutant protein when patients were administered IONIS-HTTRx;  this is the first time any drug has ever delivered such a result. Equally as excitingly, the closely-matched relationship reported indicates that the drug is likely having a powerful effect.

It is postulated that the mechanism of action of the pharmaceutical is to eradicate the messenger that relays instructions for making huntingtin, such that lacking the correct cues, the cell machinery can no longer synthesise the protein. Hence, its effects can – in theory – be silenced.

Professor Sarah Tabrizi, who led the trial, told the BBC that the results were “beyond what I’d ever hoped”. Indeed, the prospect of being able to finally treat neurodegenerative disease is tantalising, and could prove to be the biggest medical breakthrough of the decade, if not the century. After all, such maladies constitute a constellation of the most debilitating, and difficult to treat illnesses of our time. Huntington’s disease in particular typically manifests in middle age, with involuntary movements, changes in personality and dementia-like cognitive problems that become progressively worse over time; indeed, physical abilities gradually worsen until coordinated movement becomes near-impossible, and the person is unable to speak. The expected lifespan from the age of diagnosis is a maximum of 10-20 years.

In the vast majority of cases, the disease is caused by a genetic mutation, and is thus heritable. Since the mutation is dominant, a child with a carrier parent has a 50/50 chance of developing the disease themselves. However, in approximately 3% of cases, there is no obvious family history.

The trial was too small and too short to show definitively whether patients’ clinical symptoms improved, but Swiss pharmaceuticals firm Roche is expected to launch a major study aimed at testing this. If this is successful, the drug could be used not only to treat the disease once established, but also to prevent carriers from developing symptoms in the first place. Furthermore, its method of action could be copied to target other mutant proteins, such as those involved in Alzheimer’s disease. Groundbreaking, it seems, is just the word to describe this news