Huntington’s disease is an inherited brain disorder that affects every 5 in 100,000 people and causes cells in the brain to die. This often leads to difficulty controlling movements, loss of memory, inability to make decisions, a change in mood or emotions and eventually death. People with Huntington’s disease often undergo drastic changes in personality and mood that can result in depression, anger, aggression, hallucinations, and a loss of inhibition. It is a devastating disease not only for the patient but also for family members and friends. A person with late stage Huntington’s disease is often unrecognizable compared to the person they once were. Huntington’s is caused by a mutation in the gene encoding for the protein huntingtin. This mutation can be passed on from parent to offspring in an autosomal dominant fashion. What does this mean? You have two copies of every gene in your body, one that you inherited from your mother and one that you inherited from you father. These are called your alleles. In other diseases, like cystic fibrosis, you need two defective copies of the gene to get the disease, one from your mother and one from your father. This is called recessive. In a dominant disorder, you only need one defective gene in order to get the disease. If either of your parents have the problem gene, your chance of getting Huntington’s is 50%. Unfortunately, most people don’t know they have Huntington’s till later in life once they already have decided to have kids. The average age of onset for Huntington’s is 40. The function of the Huntingtin protein is still a bit of a mystery but it is important in the development and function of the brain. People with mutations have this protein begin to accumulate in their brains where it damages and prevents the normal function of the neurons.
The difficulty to date is that there has been no reliable way to determine how much of the mutant protein someone has in their brain meaning we wouldn’t be able to tell if a treatment was reducing the amount of this damaging protein. There is also no treatment for the cause of the disease, only for the symptoms. That may be about to change with new research published in the Journal of Clinical Investigation. The research team were able to measure, for the first time, the levels of mutant Huntingtin protein in the cerebrospinal fluid (CSF) of patients with Huntington’s disease. They had to develop of novel technique to measure the protein because it is present only in very low levels in the CSF of patients with the disease. The technique bound fluorescent antibodies to the Huntingtin protein in the CSF taken from the patients and counted it using a sensitive laser. Doing this, they were able to show that in patients with Huntington’s disease, the mutant protein was present and the levels of the mutant protein in people who had developed symptoms was higher than those people who had the mutation but had not developed symptoms yet. They also found that the increasing levels of the protein in the CSF related to declines in motor function and cognitive function as well as the progression of the disease.
This research provided a helpful way to measure the amount of mutant protein in the CSF but the real benefit of the technique will likely be realized in an upcoming clinical trial for a Huntington’s treatment. As mentioned before, most treatments for Huntington’s only manage the symptoms but do not slow the progression of the disease and all patients will still eventually die. This new treatment however, holds the promise of being able to reduce the levels of the mutant protein in the brain of patients and hopefully slow or reverse the disease. In order to determine if it is working, we need to be able to measure the levels of protein in these people, thus the technique. The treatment would involve the administration of a small molecule known as an siRNA that can bind to the message used to make the defective protein and prevent it from being made in the first place. While this is promising, there can be some side effects if the siRNA binds to the wrong message in the cells or if too much of the protein gets reduced. However, studies with this technique in mice and in monkeys have shown promising results and we have no reason not to expect promising results with the trial. Using the new technique described here, researchers will be able to measure how the level of the protein changes over the course of the treatment and they will also be able to best determine when to start the treatment if it gets approved for use outside of the trial. This could prove to be an exciting 2015 for people and families suffering from Huntington’s disease. Without a promising treatment, the best people with Huntington’s disease can do is go through genetic counselling in the hopes of stopping the disease from being passed on to any children they may decide to have. Let’s hope this trial, which starts soon in Vancouver, pans out.
Photo credit: “Huntington” by Frank Gaillard