Using genetics to find the best targets for treatment in Huntington's disease
Huntington’s disease (HD) is a rare, inherited, neurodegenerative disease that causes death of cells in the brain. People with HD have uncontrolled movements, problems with thinking and organising and sometimes personality changes when they get the disease and there is no cure.
To help in the search for treatments, we have been looking for genetic factors which alter the age at onset of Huntington’s disease. Tackling those genetic targets known to make onset of disease earlier might help us to treat the disease in people to delay onset.
HD is caused by an expanded CAG repeat in the huntingtin gene. Everyone has this repeat in their huntingtin gene but in most people it contains 35 CAGs or less – in people with HD the repeat is expanded to 36 or more CAGs.
How this causes disease is not understood but we do know that having this expansion produces a protein product from the gene that has an elongated tract of the amino acid glutamine. This makes the huntingtin protein sticky and it forms aggregates, inside cells in the brain, which seem to be involved in the loss of brain cells that cause the symptoms of the disease.
However, the molecular events leading to the death of cells remain unclear. We are using genetics to try and find out what those events are so we can intervene to treat the disease.
As part of a large international collaboration, we have analysed the whole genome of HD patients who have contributed to many studies in multiple countries over the past decades. Our current studies have examined DNA from over 6000 people and found several regions of the genome that are implicated in altering the age of onset of HD. These regions imply that biological pathways involved in DNA repair and manipulation in cells may be involved in altering the age of onset of HD.
This information is helping us set up new experiments to understand the molecules and mechanisms highlighted. We can generate new models and try to alter the processes that are implicated by the study using drugs and compounds that are already available in existing and novel experimental systems.
The outcome of this work will potentially provide therapeutic targets against which new treatments can be generated and eventually help to slow down or prevent HD in people.