Neurosurgical Horizons in the Treatment of Huntington's Disease: From the Laboratory to the Clinic

Presentation given by Dr. Kathleen Shannon and Dr. Jeffrey Kordower on April 21, 1996. Summary by Renette Davis.

"The sun is shining very brightly on Huntington's Disease research today."

Thus began Dr. Kathleen Shannon's presentation to about 150 guests at the HDSA Illinois Chapter Annual Brunch on April 21, 1996. Dr. Shannon, director of the Huntington's Disease Clinic at Rush-Presbyterian-St. Luke's Medical Center in Chicago, Illinois, talked briefly about the history of knowledge relating to Huntington's Disease, from Dr. Huntington's original description of the disease 150 years ago to the study of the large Huntington's population at Lake Maracaibo in Venezuela.

She then described some of the motor and cognitive signs of Huntington's Disease. Motor signs include:

The development of the disease is slow, with early signs being eye movement abnormalities, then fine motor changes, and then chorea. There are usually 3-5 years between eye movement abnormalities and chorea. The last motor signs are dystonia and parkinsonism, which is when the patient is wheelchair and bedbound.

Cognitive signs include:

Dr. Shannon talked about what causes Huntington's Disease symptoms, and what kind of therapies might be developed to eliminate those symptoms. The symptoms of a degenerative disease depend on what areas of the brain are affected. In order for transplantation to be a viable treatment, the disease must affect only a small area of the brain. In HD, the basal ganglia is the area which is affected. The basal ganglia directs normal movement, selection of appropriate action, and suppression of inappropriate action. It is also important for cognitive function.

In 1993 the gene for Huntington's Disease was discovered. It is an autosomal dominant gene with complete penetrance, which means there are no carriers of the gene. Another characteristic is anticipation with paternal transmission; i.e., the disorder usually occurs at an earlier age and is usually more severe when inherited from the father. The gene contains an unstable expanded CAG trinucleotide repeat, and the number of repeats determines whether the person has Huntington's Disease. If the number of repeats is 40 or more, the person has HD as shown below:

The cascade for Huntington's disease starts with the abnormal gene. The abnormal gene produces an abnormal protein called huntingtin. The abnormal protein causes brain cell energy failure through an increased susceptibility to excitatory brain chemical messengers. That leads to cell death.

Dr. Shannon said that researchers are looking at what could be done at each step of the cascade to keep brain cells from dying. Even if it is possible to stop brain death, however, there will still be a need to repair brain cells that have already died in the patients who now have Huntington's Disease.

At that point, Dr. Shannon turned the presentation over to Dr. Jeffrey Kordower, who is director of the Research Center for Brain Repair. Dr. Kordower said there is real reason for optimism in Huntington's Disease research today. There are outstanding committed physicians working with Huntington's Disease and a large group of basic scientists committed to trying to understand and develop treatments for HD.

Dr. Kordower said that Huntington's Disease is a fascinating challenge for scientists because they already know at the gene level what is wrong. It is the only disease where it is possible to know who will come down with symptoms before the symptoms occur, and they know the area of the brain which is affected.

It is possible to prevent degeneration of brain cells by transplanting cells that make chemicals to prevent the original cells from dying. It is also now possible to replace brain cells that have already died. Experiments have been done on animals which indicate that this may be a viable therapy for Huntington's Disease.

The scientists created an animal model for Huntington's Disease by injecting excitatory amino acids into the animals. Dr. Kordower showed slides from one experiment which was done with rats where they injected a toxin and destroyed part of the striatum. When they injected control fiberblasts, the lesions were the same. However, when they injected the toxin plus fiberblasts that make a nerve growth factor, they were able to shrink the lesions.

Not only were the scientists able to prevent the cells from dying, they were able to get the cells to improve. This was true for multiple types of cells, so they believe that this type of therapy will be able to protect the whole constellation of cells that die in Huntington's Disease. Dr. Kordower explained that the goal is to treat people, and the way to go about reaching that goal is to test the new possible therapies carefully. Physicians and scientists at Rush are actively pursuing preliminary studies leading up to clinical trials of fetal transplantation in HD.

Dr. Shannon briefly discussed pallidotomy, which is an operation that has been used with Parkinson's Disease to block the chorea which is sometimes caused when taking medication for Parkinson's. While pallidotomy may be useful in the treatment of choreic movements, the effects on other symptoms of the disease are less clear and to the extent these other symptoms (personality, behavioral, cognitive changes) contribute to the disability of HD, pallidotomy may be only a partial answer. Rush does not currently plan a pallidotomy research program for HD.

Dr. Shannon explained that there are lots of opportunities to participate in studies at Rush. They are now doing studies on new medications for Huntington's Disease, and need about 20 patients for one of those studies. She emphasized that people who sign up for clinical trials are pioneers. The risks and long term benefits of new therapies are unknown. In this type of research, the results benefit future generations, which in the case of Huntington's Disease happens to be the patient's children and grandchildren.

Dr. Shannon and Dr. Kordower then asked if members of the audience had questions. Following are some of those questions and their answers.

Question: What exactly is used in a fetal cell transplant?

Answer: A small part of the brain. If it is human tissue, it is from elective abortions. The women having the abortions sign permission for the tissue to be used. It is hard to get enough tissue from a human fetus, however, so other types of tissue, such as porcine (pig) are used instead in some studies.

Question: Is it necessary to take immunosuppressant medication after a fetal cell transplant?

Answer: Yes - for 6 months with human transplants. With porcine cells or other species it will probably be necessary to take immunosuppressant medication for life.

Question: Is there risk of transplanting viruses such as AIDS from the fetus?

Answer: The risk is very small. The research group stores fetal tissue in the lab for a number of days and runs tests against it for HIV, etc.

Question: What is actually involved in the procedure for fetal cell transplantation?

Answer: It's a very easy procedure. Small holes are made in the skull. The fetal tissue is cut up into little pieces and injected into the brain. The cells know what to do from there.

Question: Are other centers already involved in fetal cell transplants?

Answer: The center in Los Angeles has done 3 human fetal cell transplants.

Question: How do you get subjects for studies?

Answer: Dr. Shannon looks through her list of patients and contacts those who she thinks would be good candidates. She sends them an information sheet and tells them to contact her if they're interested. When people come into her office, she often suggests research projects that they might be interested in. If they don't want to participate, that doesn't impact their care. If she needs a larger supply of subjects, she puts notices in newsletters, newspapers, etc. However, she looks at her patients first.

Question: Do you prescribe Haloperidol for Huntington's Disease?

Answer: Dr. Shannon no longer prescribes Haloperidol because it really treats only chorea, and chorea is not the most disabling symptom of Huntington's Disease. Haloperidol affects cognitive function, and may make later symptoms worse.

Question: Are stimulator implantations possible for Huntington's Disease?

Answer: Stimulator implantations have been used in Parkinson's for tremor but they don't seem to be helpful in Huntington's.

Question: Do you see fetal transplantation as the best possibility right now for a cure for Huntington's Disease?

Answer: Dr. Kordower said he is very encouraged. He believes this is the time to try it. There is solid and consistent data to warrant an open trial. The data will determine if it's the best treatment. Dr. Shannon believes it is an essential stepping stone to the cure. Techniques will be refined and we will learn things about the brain. She believes there will be something soon that pre-symptomatic individuals will be able to take to prevent the onset of HD symptoms. However, there are still 25,000 people with symptoms now who will need something to restore them to a full quality of life.

Question: Should we test children to find gene carriers now?

Answer: No. Unless a compelling therapy is developed for those who have the gene, there is no reason to test children.

Question: How important is it to donate brain tissue?

Answer: Extremely important. Brain tissue provides evidence that reinforces what is done in the lab. It is also important for people who are not at-risk to donate brain tissue for use as control.

Question: Why were my son's testicles also requested?

Answer: When a man passes on Huntington's, he frequently passes on a more severe case than what he had. They want to look at the sperm to find out why some have more repeats in the Huntington's gene.

Question: How much does the political climate affect research in fetal cell transplantation?

Answer: It was not illegal to do fetal transplants before, but it was illegal to get federal funding. Clinton reversed that. If there is a change in administration, it may be reversed again.

Question: Why is fetal tissue used?

Answer: If cells are too mature, they have already sent out long connectors. When those connectors are cut, the cells die.

Question: Do you have a home page on the world wide web?

Answer: Dr. Shannon will have one soon, probably within a month. It will be part of Rush-Presbyterian-St. Luke's home page. Note: the URL for Rush is:

For more information on the talk by Dr. Shannon and Dr. Kordower, see Spring Brunch Recap from the Summer '96 issue of Hopes & Dreams, newsletter of the Illinois Chapter, Huntington's Disease Society of America.

Send comments to Renette Davis by clicking here. Last updated: Dec. 2, 2010