New drug treats crippling symptom of Huntington's disease

BACKGROUND: Huntington's disease (HD), also called Huntington's Chorea, is a progressive neurological condition passed down through families through their genes. A child of a person with Huntington's has a 50 percent chance of developing it themselves.

The condition is rare, affecting about one in 10,000 people in the United States. Huntington's disease causes brain cells, or neurons, in certain areas of the brain to degenerate, resulting in uncontrollable movements, loss of intellectual abilities and emotional problems. Symptoms of Huntington's normally present themselves when a patient is between ages 30 and 50. Those who show symptoms earlier usually have a more serious case of the disease.

According to the National Institution of Neurological Disorders and Stoke, some of the early signs of Huntington's disease include mood swings, depression, irritability, difficulty driving and learning new things.

Medications are available to treat the signs and symptoms of HD, but currently, there is no way to stop HD. However, with the discovery of the HD gene a decade-and-a-half ago, researchers are investigating how it causes the disease in the human body, so they can hopefully one day prevent it. In 2006, researchers discovered that the Huntington's gene disturbs the accumulation of cholesterol in the brain. Specifically, the protein expressed by the Huntington's gene interacts with another protein to cause the disruption. Cholesterol is crucial for the communication of brain cells so a change in cholesterol levels or their location can cause problems with motor skills, cognitive skills and speech. Finding a way to target the interaction between the proteins may lead to a targeted drug therapy.

A simple blood test can let people know if they will develop the disease or not, but since there is no cure, many opt not to have it. Patients usually die within 10 to 30 years of its onset.
PUTTING PATIENTS BACK IN CONTROL: As Huntington's disease progresses, many suffer from chorea, or jerky, involuntary movements throughout the body. Tetrabenazine (Xenazine) is the first drug approved by the FDA to treat chorea in HD patients. It works by decreasing the amount of dopamine in the brain. Dopamine is a neurotransmitter that allows certain nerve cells to communicate. In people who have HD, dopamine is overactive, resulting in the abnormal movements. By decreasing dopamine, the movements are thereby also decreased.

A randomized, double-blind, placebo-controlled clinical trial investigated the safety and effectiveness of the drug. The involuntary movements of patients who received tetrabenazine reduced on average by 25 percent. In addition, patients who took the drug were six times as likely to be considered by their doctors to have improved significantly. Sixteen sites across the county conducted the study which involved 84 patients.

Kathleen Shannon, M.D., a neurologist at Rush University Medical Center in Chicago, Ill., discusses a new drug to treat chorea, one of the most crippling symptoms of Huntington's disease.

Dr. Shannon: Huntington's disease is a hereditary disease that affects every generation of a family. There are three types of symptoms. There is a movement problem -- difficulty making movements and then movements are contaminated by extra or involuntary movements and that includes walking, balance, etc. It progresses and becomes very disabling. The second part is a behavioral problem, and by that I mean depression, irritability, anxiety, sometimes difficulty controlling the temper. Then the third part is a cognitive disorder, which is trouble with planning, organizing, thinking, memory, ultimately resulting in a person who really can't do anything for themselves physically or mentally.

What is chorea?
Dr. Shannon: Chorea comes from the Greek word for dance. That's where choreography comes from, and it refers to the one specific type of involuntary movement people with Huntington's disease have, where it's a writhing, kind of rapid, purposeless movement. The severity of chorea varies quite a bit from patient to patient. Some people have lots of it, and some people have relatively little, so there are degrees.

How does having chorea affect a person's quality of life?
Dr. Shannon: One interesting thing about chorea is many patients with chorea don't recognize they have it. I have one articulate patient who says that even when she looks at herself in the mirror,she doesn't see it. She can see it when she watches herself on video, but she doesn't see it when she looks at herself in the mirror, and she doesn't feel it; but it does interfere with movement in some patients when it's severe, and patients who know they having chorea -- not that the feeling it, but know that they have it -- may limit their activities. They may not go to a restaurant or to a movie, so in that sense it does decrease quality of life. It makes it harder to feed yourself and do those kinds of activities.

Prior to the drug tetrabenazine (Xenazine), what was done to treat chorea?
Dr. Shannon: There were no FDA approved treatments. There are medicines that people had kind of tried over the years and with some success. Medicines were often used to treat schizophrenia would be useful to control chorea. There is an anti-Parkinson's drug called Amantadine that sometimes helps control chorea, so it's been kind of a trial and error way of managing the symptom.

What is different about Xenazine?
Dr. Shannon: Tetrabenazine is more potent at controlling the chorea. Virtually everyone with significant Chorea will have a response, whereas with other drugs that we've used in the past, not everyone responds, and the response isn't always as complete. So the tetrabenazine is a much more effective treatment for severe chorea.

How does it work?
Dr. Shannon:
Chorea in Huntington's disease is related to an increased sensitivity of the brain to the chemical dopamine, which is a you know, brain cells use chemicals to communicate. The traditional medicines block dopamine's effects in the nervous system. Xenazine depletes the nervous system of dopamine, so instead of the dopamine being released and being blocked, it's actually depleted so it can't be released, and for some reason that's more effective than simply blocking the dopamine.

Are there any side effects of depleting dopamine completely?
Dr. Shannon:
Yes. Powerful medicines have powerful side effects. This is not for sissies, this drug. It can cause significant depression. It causes people to feel slowed down or sluggish. It can cause people to be sleepy, so it can be difficult to use. The trick for using the drug is to start it at a really teeny tiny dose and increase it very gradually and keep in pretty constant contact with the patients to make sure everythings going okay.

Is this the kind of drug that you kind of have to evaluate on a patient to patient basis; you want to make sure that the benefits outweigh the risks?
Dr. Shannon:
Exactly. You can't tell ahead of time so much. if a person has a history of depression, that might not be a very good person to try on tetrabenazine, but you can't always predict, so that's why you need to really have a system for the patient being able to phone and talk to someone and report how they're feeling so that the dose can be adjusted. In between visits to the office, for example, you need to keep in really close contact with patients.

What do the results from the clinical trial show in terms of how effective the drug is?
Dr. Shannon: It was significantly effective; really substantial improvements in the presence of chorea and how severe it was when it happened; but it did have side effects. There was a suicide in the study in a person that wasn't thought to be suicidal, and there was depression in the study and sleepiness, so again, it's a really powerful drug with powerful side effects.

Even though this drug isn't a cure for Huntington's disease, why is this drug so important for people suffering from it?
Dr. Shannon:
It's important for people to understand that the Huntington's disease has many, many symptoms and chorea is the only one. This treatment actually doesn't improve anything except chorea, and in fact, in the study, some things were a little bit worse. The functional state, how well people were able to care for themselves was a little bit worse, and thinking and memory was a little bit worse, and mood was a little bit worse, and so that speaks for making certain that you evaluate the risk to benefit ratio individually in each patient. People with Huntington's disease are very anxious for any new treatment, particularly if it's something that would be a cure for the disease. This is not a cure. It simply covers up one of the symptoms of the disease, but when you have an incurable disease, anything that improves your quality of life is a welcome addition to the pharmaceutical armamentarium, so anything that makes people able to go to a movie or to go out to a restaurant with their children is an important thing for them.

Have you seen a significant improvement in Mary Born?
Dr. Shannon:
She's been on tetrabenazine for a while. She's been getting it from Canada and before that from Ireland, I believe. She was someone who really didn't want to go out. She wanted to not be seen in public because she was concerned about the way that she looked, and once she started on tetrabenazine, she was able to go out and be in public again, so for her that was a really important thing.

Patients with Huntington's disease have the verbal and motor skills changes, but do they mentally still understand everything that's going on around them and understand their condition?
Dr. Shannon: It can be hard to know how much people understand because people with Huntington's have trouble expressing their feelings. They have trouble coming up with the right words. They do lose cognitive function progressively from early on in the disease. They lose the ability to express their feelings, to plan things, to organize things, to multi-task and so it can be difficult to know how intact they are, but unlike something like Alzheimer's disease, their memory and other aspects of thinking are preserved for a relatively long time. They don't lose memory function until relatively late in the disease. It's mainly really high level thinking.

Is Mary's case not as severe as other Huntington's patients?
Dr. Shannon:
No, I don't think that that's the case. Actually, you don't see chorea because she's medicated to stop the Chorea, but she's had a lot of changes in her life. She has got a good family and she's a good person and so she copes better than many people would, but she's got significant impairment and disability.

What's on the horizon for Huntington's disease?
Dr. Shannon: There's a lot of interest in Huntington's disease, because we have the gene. You can put the gene in animals and get a good model of the illness. It's fairly easy and quick to test treatments, so there are a number of things that have been identified in animal studies that look like they'd be easily tolerated in people, and that would be easy to give to people, and might potentially slow down the degeneration of the disease and therefore slow down the progressive worsening our patients have. We're currently enrolling research subjects into a large study of co-enzyme COQ-10, which is a health food supplement that is showing some preliminary evidence that it might be useful. There's interest in high doses of creatine, which is another health food supplement. This is an orphan disease and because it's an orphan disease, there are not a lot of drug companies lining up to invent new treatments for Huntington's disease, so to have even two clinical trials like this is really exciting for us, and really exciting for our patients -- new things that we hope might slow disease progression.

What's is the definition of an orphan disease?
Dr. Shannon:
Less than 200,000 people affected, I think, is the current definition.

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