Huntington's disease
Fifteen years after the discovery of the gene that causes Huntington's we still don't have a clear understanding of this incredibly complex disease.
When I grow up, my mind and body will slowly deteriorate until I choke to death trying to swallow.
–Huntington Society of Canada public service announcement
As these chilling words testify, a diagnosis of Huntington's disease is currently a dire sentence. The inherited disease, which primarily affects adults, causes certain parts of the brain to degenerate. It begins with uncontrollable body movements, and complications associated with severe impairment of motor function ultimately lead to death. Such drugs as antidepressants deal with some of the symptoms, but there is no cure for Huntington's disease. On average, patients die within 15 to 20 years of diagnosis.
Framed by a panoramic view of the University of Alberta Hospital from her office in the Department of Pharmacology, Dr. Simonetta Sipione explains the challenges researchers have faced in developing a treatment for Huntington's disease. When the gene that causes it was discovered in 1993, many hoped that the information would lead to an understanding of the disease within a few years. But almost fifteen years later, researchers still don't know how a mutation in this one gene causes so many severe symptoms. What is clear is that much of normal cell physiology is dysfunctional in the nerve cells of people who have Huntington's disease. For example, the energy-producing centres of the cell (the mitochondria) don't function properly. Cell signalling (the way a cell converts a stimulus into an appropriate action) is also impaired.
Dr. Sipione often uses an analogy when explaining what happens in Huntington's cells. "Imagine a complex of dominoes. A ball hits two or three initial dominoes, but then each of these tips over a string of other dominoes. It's a cascade effect. If you imagine that the ball is mutant huntingtin (the protein produced by the HD gene) and each domino is a cell function, at a certain point in the cascade it's very difficult for researchers to determine what's primarily due to mutant huntingtin, and what's just a consequence of general cell dysfunction."
Scientists would like to identify the very early changes induced by Huntington's disease, as these would be the best targets for therapies. Dr. Sipione may have stumbled upon one of these early changes in 2002 while completing her post-doctoral work at the University of Milan. In an experiment designed to identify all the genes that are turned on and off upon activation of the mutant huntingtin protein, she observed that several genes involved in producing cholesterol didn't function normally. Many of the impaired pathways in Huntington's cells could therefore be linked to the reduced availability of cholesterol.
This research is her "pet project", and she now returns to it as a new AHFMR Scholar. She began setting up her lab last September. Pending the arrival of her new graduate students early this summer, Dr. Sipione is still actively involved in running her own experiments, and she dons her white lab coat almost daily. Her first questions are whether low cholesterol levels actually result in altered cell signalling in Huntington's disease, and whether restoring cholesterol to normal levels can restore proper cell signalling.
Despite indications that cholesterol (or the lack of it) may play a central role in the development of Huntington's disease, Dr. Sipione stresses that treatment would not involve simply supplying patients with more cholesterol in their diets. Dietary cholesterol cannot enter the brain. The key to treatment will be a better understanding of how the production of cholesterol in the brain is controlled. Even then, because Huntington's is such a complex disease, Dr. Sipione believes that future treatment will likely involve administering a combination of drugs, or targeting a set of pathways simultaneously. This reality forces her to be cautious in predicting when patients might expect a cure.
But she is also optimistic, knowing that scientific progress is exponential: one discovery leads many groups to start approaching the question from different angles. Dr. Sipione is certainly ready.