Issue 95, December 2006
by Katie Reid
On June 16th 2006 researchers at the centre for Molecular Medicine and Therapeutics in Vancouver, BC provided groundbreaking evidence of preventing the appearance of the symptoms for Huntington Disease (HD) in a mouse, offering hope that the disease can be relieved in humans.
"It represents a major research milestone and moves us closer to finding effective treatment for this disorder" says Don Lamont, CEO & Executive Director of the Huntington Society of Canada (HSC).
"Our families live on a 'tightrope' waiting for an effective treatment or cure for HD" says Lamont. "The discovery provides hope for the Huntington community - most of all, hope that their children will not have to suffer the devastation of this inherited disease."
Published in Cell Journal, Dr. Michael Hayden and colleagues demonstrated that by preventing the cleavage of the mutant huntingtin protein responsible for Huntington Disease in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function.
"Ten years ago, we discovered that huntingtin is cleaved by 'molecular scissors' which led to the hypothesis that cleavage of huntingtin may play a key role in causing Huntington Disease", said
Dr. Michael Hayden, Director and Senior Scientist at the University of British Columbia's Centre for Molecular Medicine and Therapeutics (CMMT).
Now a decade later, this hypothesis has resulted in a landmark discovery. "This is a monumental effort that provides the most compelling evidence of this hypothesis to date", said Dr Marian DiFiglia, Professor in Neurology, Massachusetts General Hospital, Harvard Medical School and one of the world's leading experts on Huntington Disease. "Dr Hayden and his team have shown in convincing fashion that many of the changes seen in HD patients can be erased in HD mice simply by engineering a mutation into the disease gene that prevents the protein from getting cleaved at a specific site".
To explore the role of cleavage, Dr. Hayden's team established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. In the study, researchers confirmed that the deadly cleavage is caused by a key enzyme called caspase-6. By blocking the action of this target, they showed that the mouse did not develop any symptoms of Huntington disease.
Hayden's team is now trying to test this model of prevention in a mouse using drug inhibitors and then ultimately in humans. "Our findings are important because they tell us exactly what we need to do next", said Dr. Rona Graham, Post Doctoral Fellow at the CMMT and lead author in the study.
CHDI Inc. is also pursuing programs searching for drug inhibitors for the enzyme Caspase-6, while also looking at several other proteases and reagents as part of this broader effort.
This work is also pivotal for the individuals and families affected by Huntington disease.
"Patients of this disease should know that this is a research milestone for all and that this work brings the field closer to finding effective treatment for a devastating disorder", said Dr. DiFiglia.
HSC is honoured to have a long-term association with Dr. Hayden. Dr. Hayden has numerous scientific achievements in HD, including the establishment of CMMT, which conducts one of the most comprehensive HD research programs in Canada. We applaud Dr Hayden's lifelong and relentless search for a cure and this signal breakthrough in creating "A World Free From Huntington's". This momentous discovery adds another milestone of success in the history of Huntington's research in Canada. It is a testament to the value of philanthropic investments in the worldwide search for a cure for HD.
While families wait for an effective treatment or cure, philanthropic giving also enables the Huntington Society of Canada to strengthen and support generations of families as they manage the progressive losses with each stage of the disease.
"Horizon" Huntington Society of Canada No.120 Fall 2006