EDGE Services Newsletter March 2018

A landmark trial for Huntington’s disease has announced
positive results, suggesting that an experimental drug
could become the first to slow the progression of the
devastating genetic illness.
The results have been hailed as “enormously significant”
because it is the first time any drug has been shown
to suppress the effects of the Huntington’s mutation
that causes irreversible damage to the brain. Current
treatments only help with symptoms, rather than slowing
the disease’s progression.
Prof Sarah Tabrizi, director of University College London’s
Huntington’s Disease Centre who led the phase 1 trial,
said the results were “beyond what I’d ever hoped ... The
results of this trial are of ground-breaking importance for
Huntington’s disease patients and families,” she said.
The results have also caused ripples of excitement
across the scientific world because the drug, which is a
synthetic strand of DNA, could potentially be adapted to
target other currently incurable brain disorders such as
Alzheimer’s and Parkinson’s. The Swiss pharmaceutical
giant Roche has paid a $45m licence fee to take the drug
forward to clinical use.
Huntington’s is a degenerative disease caused by a
single gene defect that is passed down through families.
The first symptoms, which typically appear in middle
age, include mood swings, anger and depression. Later
patients develop uncontrolled jerky movements, dementia
and ultimately paralysis. Some people die within a
decade of diagnosis.
“Most of our patients know what’s in their future,” said
Ed Wild, a UCL scientist and consultant neurologist at
the National Hospital for Neurology and Neurosurgery in
London, who administered the drug in the trial.
The mutant Huntington’s gene contains instructions for
cells to make a toxic protein, called huntingtin. This code
is copied by a messenger molecule and dispatched to the
cell’s protein-making machinery. The drug, called Ionis-
HTTRx, works by intercepting the messenger molecule
and destroying it before the harmful protein can be made,
effectively silencing the effects of the mutant gene.
To deliver the drug to the brain, it has to be injected into
the fluid around the spine using a four-inch needle.
Prof John Hardy, a neuroscientist at UCL who was not
involved in the trial, said: “If I’d have been asked five
years ago if this could work, I would have absolutely said
no. The fact that it does work is really remarkable.”
The trial involved 46 men and women with early stage
Huntington’s disease in the UK, Germany and Canada.
The patients were given four spinal injections one month
apart and the drug dose was increased at each session;
roughly a quarter of participants had a placebo injection.
After being given the drug, the concentration of harmful
protein in the spinal cord fluid dropped significantly and
in proportion with the strength of the dose. This kind of
Spring 2018 Newsletter 3
New Trial shows Huntington’s Drug Slow
Progress of Disease
closely matched relationship normally indicates a drug is
having a powerful effect.
“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,” said Tabrizi. “This is
probably the most significant moment in the history of
Huntington’s since the gene [was isolated].”
The trial was too small, and not long enough, to show
whether patients’ clinical symptoms improved, but Roche
is now expected to launch a major trial aimed at testing
this.
If the future trial is successful, Tabrizi believes the drug
could ultimately be used in people with the Huntington’s
gene before they become ill, possibly stopping symptoms
ever occurring. “They may just need a pulse every three
to four months,” she said. “One day we want to prevent
the disease.”
The drug, developed by the California biotech firm Ionis
Pharmaceuticals, is a synthetic single strand of DNA
customised to latch onto the huntingtin messenger
molecule.
The unexpected success raises the tantalising possibility
that a similar approach might work for other degenerative
brain disorders. “The drug’s like Lego,” said Wild. “You
can target [any protein].”
For instance, a similar synthetic strand of DNA could be
made to target the messenger that produces misshapen
amyloid or tau proteins in Alzheimer’s.
“Huntington’s alone is exciting enough,” said Hardy, who
first proposed that amyloid proteins play a central role in
Alzheimer’s. “I don’t want to overstate this too much, but
if it works for one, why can’t it work for a lot of them? I am
very, very excited.”
Prof Giovanna Mallucci, associate director of UK
Dementia Research Institute at the University of
Cambridge, described the work as a “tremendous step
forward” for individuals with Huntington’s disease and
their families.
“Clearly, there will be much interest into whether it can
be applied to the treatment of other neurodegenerative
diseases like Alzheimer’s,” she added. However, she
said that in the case of most other disorders the genetic
causes are complex and less well understood, making
them potentially harder to target.
About 10,000 people in the UK have the condition and
about 25,000 are at risk. Most people with Huntington’s
inherited the gene from a parent, but about one in five
patients have no known family history of the disease.
The full results of the trial are expected to be published in
a scientific journal next year. To read more on this article
visit https://www.theguardian.com/science
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