Toronto — Canadian researchers have unlocked the molecular secret that eliminates the symptoms of Huntington's disease in mice, a landmark discovery that is offering new hope for preventing the devastating effects of the disorder in humans.
A team of scientists from the University of British Columbia have discovered that by preventing the cutting, or “cleavage,” of a protein responsible for Huntington's in genetically altered mice, the symptoms of the disease do not develop and the animals exhibit normal brain function.
“We've found a way to cure this disease in a mouse,” said principal investigator Dr. Michael Hayden, director of UBC's Centre for Molecular Medicine and Therapeutics. “We're taking every step that we can to develop similar approaches in humans.”
Huntington's disease is an inherited neurological disorder that causes progressive loss of physical control, alterations in behaviour and emotions, mental deterioration and ultimately death.
The incurable condition affects one in every 10,000 Canadians, with symptoms typically appearing in the late 30s, although they may begin showing up earlier or later in life. Every child of a parent with Huntington's has a 50 per cent risk of inheriting the gene that leads to the disease. There are no effective treatments.
Liz Manique of Toronto, who has watched Huntington's disease slowly steal her father's mind and body over the last 17 years, called the discovery “fantastic, wonderful news.”
“I know we're not there yet and there's still a long way to go, but it's just that little sense of ‘Wow, something's happening, we've taken another step and we're getting that much closer.'
“For any family with Huntington's, it's a huge, huge breakthrough,” said Manique, 32, who had a 50-50 chance of inheriting the defective gene, but was found through testing not to carry it. “For other people who are at risk today and for future generations . . . it's hope for them, it's hope for the future.”
The discovery, published Friday in the prestigious scientific journal Cell, is the culmination of years of painstaking scientific investigation that began when the UBC team developed mice with the mutated gene that causes the same neurological and physical symptoms seen in humans with Huntington's disease.
In 1996, the UBC lab found that a key protein, called huntingtin, is sliced in several spots by “molecular scissors,” leading them to hypothesize that it was this cleavage that led to symptoms. Over the next decade, the researchers worked to identify the specific cleavage site — and found that it was caused by an enzyme known as caspase-6.
By blocking the enzyme's action, the team was able to stop the mice from developing symptoms.
“When we inhibited caspase-6, these mice were incredible,” Hayden said Friday. “They never developed the disease, and in fact their brains were quite resistant to many toxins.”
The next step involves looking for a chemical compound that will block the effects of caspase-6, then test it in the Huntington's mice. If successful, the candidate drug would then be tested in humans.
“We know what to do now,” said Dr. Hayden. “It's not as though we don't know what the next steps are. They're very pragmatic, very practical.
“This represents a very hot target for treatment for this disease . . . “I'd like to think we'll be ready to go into human trials within five years.”
Harvard neurobiologist Marian DiFiglia, a world-renowned Huntington's researcher, called the finding “very important” and “extremely intriguing.”
“It really allows for more focused attention” by other Huntington's researchers around the world, DiFiglia said in an interview from Boston, noting that she and other scientists had been following the Canadian team's progress with “great enthusiasm.”
“To see it finally published is very exciting for all of us.”
Don Lamont, CEO of the Huntington Society of Canada, agreed the discovery gives direction to future research for a treatment or cure for people with the disease.
“And that means that someday we're going to have a party,” said Mr. Lamont. “And at the party we're going to have long-suffering families, we're going to have donors and researchers and we're going to toast to the fact that we have found a solution here.”
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