Research Frontiers
Chapter 2, Part 3

Approaching HD

According to Dr. Cattaneo, to be conceptualized correctly, HD must be seen as a cascade in which every single disease event leads to more events that cause further dysfunction and damage (see Figure AH-0.) In some way, HD researchers are lucky because they have a definite single starting point of the disease: a CAG expansion in the Huntington gene. Cattaneo agrees that the genetic nature of HD makes it easier to research than other neurodegenerative diseases, which can have varying genetic and environmental causes. However, the disease cascade has yet to be completely figured out, and Cattaneo stresses that it will be important not only to find a majority of the disease events, but also to arrange them in the correct temporal order; that is, to figure out when each dysfunction occurs, what causes it, and what other dysfunctions it causes itself. As is evident from Figure AH-0, this will not be an easy task.

Researchers in Dr. Cattaneo´s lab are already working on putting together the schematic cascade, but Cattaneo says that the work is difficult since "every result leads to more experimentation." With every new mechanism she and the researchers discover, there is more they need to find out about its causes and effects. Cattaneo says that often, "your brain goes faster than your hands," and while she or her colleagues may form hypotheses and ideas rapidly, the funding and time may not allow for immediate experimentation to follow up on those ideas. However, one researcher in the lab, Chiara Zuccato, was recently very successful in figuring out a very important aspect of the disease cascade. After learning that normal huntingtin protein increases the amounts of brain-derived neurotrophic factor (BDNF) in nerve cells, she set out to find the mechanism by which it does so. Zuccato found that normal huntingtin increases the production of BDNF by indirectly inhibiting a molecule called NRSE, which normally prevents the production of BDNF (this finding will be explained in more detail in a later section).

Because BDNF is a protective growth factor in the brain and is depleted in the nerve cells of people with HD, researchers in Dr. Cattaneo´s lab are now focusing their energies on the functions of normal huntingtin and what prevents it from performing these functions in people with HD. This approach is different from the classic research approach that has typically focused only on mutant huntingtin. However, mutant and normal huntingtin may be linked earlier on in the disease cascade and Cattaneo´s lab is now on a quest to figure out how mutant huntingtin´s toxicity could cause normal huntingtin´s loss of function in HD.

Unfortunately, BDNF production is only one of many cellular processes that are disturbed in HD, and Cattaneo says real progress will be made when researchers are finally able to link together all the dysfunctions in a cause-and-effect relationship. Transcriptional dysregulation is a major disease mechanism in HD that affects the production of proteins needed by nerve cells (one of these is BDNF, mentioned above). Mitochondrial dysfunction, which causes abnormalities in energy metabolism, is another major disease mechanism. (For more information on problems with energy metabolism in HD, click here.) As of now, researchers only understand bits and pieces of each of these major mechanisms, and Cattaneo believes that mapping out precisely what events lead to these dysfunctions will be crucial in understanding HD and developing a cure.

Because HD involves a complicated cascade of events, Dr. Cattaneo believes that an effective cure will actually involve a combination of treatments. She is very hopeful about the use of new techniques such as RNA interference, which attack the disease as close as possible to the beginning of the cascade by "silencing" the mutant Huntington gene. However, Cattaneo doesn´t think that such techniques will ever be able to fully block the production of the mutant huntingtin protein. (For more information on RNA interference, click here.) Cattaneo says that "a cure with only one strategy is not realistic; to battle HD you need a more global approach." In the future, she believes that the most successful therapy, which could turn into a cure, will involve different types of treatments at different stages of the disease. According to Cattaneo, these treatments will ideally begin before the onset of symptoms and change accordingly as the disease progresses from the nerve cell dysfunction stage to the nerve cell death stage. Future treatment of HD may include:

• Stage I: Early treatment with RNA interference to prevent expression of mutant huntingtin; continues throughout the following stages.
• Stage II: Dysfunction of nerve cells combated by drugs that prevent toxic functions of mutant huntingtin and drugs that restore the functions of normal huntingtin.
• Stage III: Nerve cell death combated by cell replacement therapy (possibly with the use of stem cells) as well as protective strategies involving therapy with growth factors such as BDNF.

However, because potential drugs will be used to combat the disease at different time points in different individuals, the researchers will need biomarkers. Biomarkers are biological indicators that can be measured in patients to determine the severity of disease and to show whether drugs are effective in specific stages of the disease. Measuring the severity of symptoms is not sufficient because symptoms can vary so widely between patients and between stages of the disease. A possible biomarker that the Cattaneo lab is considering using is the level and activity of the A_2A receptor, a receptor molecule that is expressed by nerve cells in the striatum and becomes more active in the presence of mutant huntingtin. Another possibility involves measuring levels of BDNF, which can also be used to track the progression and severity of the disease.

Dr. Cattaneo´s lab tries to simultaneously identify drug targets as they learn about new disease mechanisms. She stresses that successful drug development cannot happen without a deep understanding of the disease mechanism that the drug is meant to attack. Therefore, she believes that studies on compounds such as nutritional supplements and their effects in people with HD are not as promising at they may seem since most of the studies are conducted without an understanding of how the supplements exert their effects. An understanding of the disease mechanism is essential to picking drug targets - molecules that the drug will act on to alter some pathway - that will be both effective and safe. The drug must act early enough in the pathway to successfully stop the disease cascade, but it must also be specific enough so that it does not cause significant side effects.

Last Modified: 04/12/2007

An educational product of HOPES, not to be used in place of medical care. For more information about HOPES, click on the Logo. To contact HOPES with comments or questions, click here.