Huntington's disease is an inherited disorder in which mutant forms of the huntingtin protein damage nerve cells in the brain.
The new drug, Ionis-HTTRx, was shown to be safe in humans and lowered levels of mutant huntingtin protein in the nervous systems of trial participants.
"The results of this trial are of groundbreaking importance for Huntington's disease patients and families," said Sarah Tabrizi, director of University College London's Huntington's Disease Centre, who led the trial. "The key now is to move quickly to a larger trial to test whether the drug slows disease progression."
The trial involved 46 patients at early stages of the disease who were enrolled across nine centers in the UK, Germany and Canada. Initial results were announced Monday.
Each patient received four doses of either the new drug or a placebo, injected directly into spinal fluid so it could easily reach the brain. For those receiving the drug, the dose was increased over time, and safety was monitored throughout, according to a statement.
Concentrations of the toxic protein were measured in the patients' spinal fluid before and after the injections.
Among people receiving Ionis-HTTRx, the team saw a significant decline in levels of mutant huntingtin, which causes symptoms of the disease, with higher doses having greater impact. This is the first time the protein has been lowered in patients with the condition.
"The results are encouraging, as it shows delivering therapeutic agents of this type is feasible and well-tolerated and the treatment has done what it said it would: namely, drop the relevant protein levels," said Roger Barker, professor of clinical neuroscience and honorary consultant neurologist at the University of Cambridge, who worked with six patients involved in the trial.
"The question is whether this is enough to make a difference to patients and their clinical course, and that we will have to wait for bigger trials," he said.
The team now plans to conduct a larger-scale trial in hundreds of patients across multiple centers, said Ed Wild, a principal researcher at UCL's Huntington's Disease Centre, who worked on the trial with Tabrizi.
Hunting down huntingtin
Huntington's disease is an inherited neurodegenerative disorder in which nerve cells in the brain are damaged, causing uncontrolled movements, changes in behavior and emotions, and altered cognition.
The disease typically begins affecting people between the ages of 30 and 50 and gets progressively worse over time. Children of a parent with the disease have a 50% chance of inheriting the mutant gene.
An estimated 30,000 Americans
are living with the disease. About 10,000 people in the UK have it, and a further 25,000 are at risk.
The condition is caused by a mutation in the huntingtin gene, which encodes the huntingtin protein, which is needed for normal development before birth and thought to help brain cells function, though the exact function is unknown
. The mutant form of this protein accumulates and binds together to become toxic
to certain brain cells, eventually killing them.
A drug with the ability to reduce levels of the toxic protein would mean progression of the disease could be slowed or even stopped.
"The details of this study have not been peer-reviewed or published yet, so the scientific community simply does not know yet how robust the findings are," noted Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, who was not involved in the research.
"With that caveat in mind, the approach used in this trial has excellent potential to prevent Huntington's disease," she said, "and if the next stage of larger trials live up to their promise, this will be a breakthrough."
How the drug works
The drug consists of a single strand of DNA that targets genetic material within brain cells, called mRNA, that helps translate genes into proteins.
In this case, the drug specifically sought out mRNA that helps translate huntingtin genes into huntingtin proteins and stopped production of the protein -- both the healthy and toxic forms.
"Less of the protein is made," Wild said, adding that the healthy form of the protein is known to play a vital role in early childhood development but not necessarily during adulthood, whereas the toxic form damages nerve cells in adults. "That protein is the cause of all of the problems" in Huntington's disease.
It's hoped this form of drug could be adapted to target proteins in other currently incurable brain disorders, such as Alzheimer's disease.
By changing the DNA sequence in the drug, researchers can target any mRNA, Wild said. In other neurodegenerative diseases, "there is at least one protein you would like to partially reduce," he said. One example is tau protein in Alzheimer's disease. "This is proof of principle you can inject these drugs into spinal fluid; they get into the brain and reduce harmful proteins."
"This is a potential game-changer, not only for Huntington's disease patients but also for genomic medicine in general," said Philippa Brice of health policy think tank the PHG Foundation.
"Though more work needs to be done, if gene silencing lives up to this promise, we could be on the brink of some of the personalized treatments that patients with severe genetic diseases need so badly. But this will also raise further questions for society and for policy-makers about how best to use such a powerful technique," Brice said.
The drug was developed by Ionis Pharmaceuticals but has been taken over by Roche, which will lead the development of the next, larger trial and handle future licensing of the drug, Wild said. The full results of the trial and plans for future trials will be presented next year.