Also called ubiquinone, or CoQ10. CoQ10 is a nutritional supplement that acts as an antioxidant and is an important molecule involved in the respiratory chain.More
Huntington’s Disease (HD) is associated with a genetic mutation that results in an expanded polyglutamine chain in the huntingtin protein. In HD, huntingtin becomes a misfolded protein, which can cause many problems for the nerve cell. Scientists have not yet found a straightforward way to explain how a single genetic mutation can lead to the complex symptoms of HD. It is thought that misfolded huntingtin damages the nerve cell in many different ways.
One proposed mechanism suggests that misfolded huntingtin damages an organelle in the nerve cell called the mitochondrion. Mitochondria are important because they help the cell produce energy and regulate the number of free radicals in the cell. When the mitochondria are not working correctly, oxidative damage occurs in the cell because there are too many free radicals. This is thought to contribute to nerve cell death in HD. Therapies that reduce the amount of free radicals in the nerve cell might prevent some HD symptoms.
One potential treatment to reduce free radicals involves a molecule called coenzyme-Q10, which is naturally produced throughout the body. It plays a role in the electron transport chain and helps produce ATP, the cell’s major source of energy. (For more information on coenzyme-Q10 and the electron transport chain, click here.) Coenzyme-Q10 also reduces oxidative damage by interacting directly with free radicals, inactivating them so they cannot damage the cell. The level of coenzyme-Q10 in the brains of HD patients is lower than normal, potentially reducing the ability of affected nerve cells to manage free radicals that accumulate. Because the nerve cells can no longer deactivate all of the free radicals, they become damaged. Drug supplements may be useful to raise the level of coenzyme-Q10 in the brain and prevent the damage caused by free radicals.
Initial Findings on Coenzyme-Q10^
This section describes several that tested the effects of coenzyme-Q10 treatment in both humans and mice. The studies show that coenzyme-Q10 is at least somewhat effective in delaying the symptoms of HD and increasing survival, and could serve as a potential treatment for HD and other neurodegenerative disorders.
Ferrante, et al. (2002) tested coenzyme-Q10 as a treatment in a mouse model of late stage HD. In this study, they found that coenzyme-Q10 given to transgenic mice increased survival by 14.5%. Human trials did not show that coenzyme-Q10 significantly affects survival, so it was thought that coenzyme-Q10 would not make an effective treatment for HD patients. Later research that studied the effects of coenzyme-Q10 in human patients with neurodegenerative disorders similar to HD, such as Parkinson’s disease and ALS, showed that higher doses of coenzyme-Q10 than those previously used produced more promising results. The patients had a significantly declined rate of nerve cell death and symptom progression. (For more information on other neurodegenerative and related diseases, click here.)
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at various sites in the United States and Canada. The trial was done to test the efficacy of coenzyme-Q10 and remacemide, an anti-glutamate drug. The participants were monitored between July 1997 and June 1998 and were assigned to four different treatments:
- 25% received remacemide
- 25% received coenzyme-Q10
- 25% received a combination of remacemide and coenzyme-Q10
- 25% received a placebo (no medication at all)
The primary measure of the drug’s effectiveness was change in Total Functional Capacity (TFC) of the people with HD. TFC is a standardized scale used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The TFC scale ranges from 13 (normal) to 0 (severe disability). The average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC. However, subjects treated with coenzyme-Q10 showed a delayed decline in the TFC compared to subjects who were not treated translating into approximately one more year of independence for people with HD. The supplement was well-tolerated by the study participants and showed no adverse effects on the participant’s other capacities. No changes in the decline in TFC relative to the placebo group were seen in the participants treated with remacemide. However, improvements in chorea were observed. (For more information on remacemide, an anti-glutamate drug, click here.)
The researchers concluded that although there was a trend toward slowing of the progression of HD with coenzyme-Q10 treatment, the effects were not large enough to recommend coenzyme-Q10 as a treatment for early HD. In part, this is because the financial costs of coenzyme-Q10 are considerable. Since coenzyme-Q10 is a nutritional supplement, it is worth remembering that it is not subjected to the same quality and content regulations as pharmaceutical drugs are. Different brands and formulations of coenzyme-Q10 may differ chemically or may contain additives, and there is little information about how these different contents might affect a person with HD. Finally, it should be emphasized that the findings of this study are not applicable to people at risk for HD, or for people at the intermediate or advanced stages of HD.
Nevertheless, the results of the study suggest that therapies that affect the energy supply in cells can affect the course of HD. Additional studies are called for to identify dosage effects and to study effectiveness for people in different stages of HD.
Koroshetz, et al. (1997) treated 18 early-stage HD patients with oral coenzyme-Q10 for 2 to 8 weeks. The patients were recruited from the Massachusetts General Hospital HD Unit and were all able to walk, with half of them still working. Brain lactate level was used as the criteria to measure the effectiveness of the supplement. They hypothesized that treatment with coenzyme-Q10 could increase the efficiency of the respiratory chain, and consequently, lower lactate levels. (For more on lactate, click here.)
The researchers discovered that upon treatment with coenzyme-Q10, the participants experienced significant decreases in brain lactate levels. Lactate levels reversed back to their original levels following withdrawal of therapy, indicating that the findings were indeed due to coenzyme-Q10 treatment. This study supports the theory that coenzyme-Q10 could increase the amount of energy available in cells, perhaps by increasing the efficiency of the respiratory chain.
Smith, et al. (2006) tested higher doses of coenzyme-Q10 with a late stage HD mouse model. This model demonstrated some features of human HD, including progressive loss of motor function. They also compared two commercially-available preparations of coenzyme-Q10, one from a company called Tishcon and one from a company called Chemco. The researchers administered different doses of each substance, seeking an optimal dosage to treat HD.
Results showed that higher doses of coenzyme-Q10 significantly slowed the progression of HD symptoms, such as declining motor performance and grip strength. Smith tested several different doses and found that for the Chemco formulation of coenzyme-Q10, 5000 mg/kg/day was the most effective dosage in extending the lifespan of HD mice. Tishcon coenzyme-Q10 extended survival by a greater amount and at a lower dosage of 1000 mg/kg/day. Moreover, HD mice treated with higher doses of coenzyme-Q10 did not lose as much weight, have as much nerve cell death, or form as many huntingtin aggregates as untreated HD mice. Administering high doses of coenzyme-Q10 to mice in the form of a pellet significantly raised the level of coenzyme-Q10 in their bloodstream and nerve cells. These findings suggest that oral administration of the drug would be effective. Finally, high doses of coenzyme-Q10 also significantly reduced the amount of OH8dG (8-hydroxydeoxyguanosine) in the brain. OH8dG is a molecule that appears in unusually high concentrations in the brains of HD patients, and is associated with oxidative stress in the nerve cell. In summary, this study shows that high doses of coenzyme-Q10 can prevent some motor symptoms, prolong lifespan, and reduce oxidative stress and nerve cell death in HD mice. However, doses that are too high are less effective, possibly because of side effects.
In comparing the effectiveness of two commercially available coenzyme-Q10 preparations, the study found that the supplement produced by Tishcon was 5 times more effective in extending lifespan than that produced by Chemco. More of the coenzyme-Q10 in the Tishcon pellet was absorbed into the bloodstream in comparison to the Chemco pellet. It is important to remember that coenzyme-Q10 is a nutritional supplement and can be bought in many different prepared forms. Nutritional supplements are not regulated by Food & Drug Administration (FDA) guidelines Often there is little standardization and poor quality control for these supplements. Little is known about how each of these prepared forms may affect HD patients differently, and so more comparative studies are needed.
The Cure HD Initiative (CHDI), a nonprofit drug development research organization for HD, has recently begun to work on creating treatments for HD using coenzyme-Q10. On August 2, 2006 CHDI announced a partnership with Edison Pharmaceuticals, Inc. Edison is a small company that specializes in drug development for diseases related to problems with mitochondria, oxidative damage, and energy levels in the cell. This partnership will be an opportunity for Edison to specifically focus on oxidative damage in HD. The partnership hopes to develop a second generation coenzyme-Q10 molecule to be used to treat HD. Scientists at Edison Pharmaceuticals will contribute their expertise in the biology and pharmacology of free radicals and oxidative damage, while members of CHDI Foundation will contribute their expertise in HD and drug development.
Earlier in 2009, the Huntington Study Group received funding from the NIH to test safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not show any motor signs of HD. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials). The study will be conducted at 10 clinical sites throughout the nation and is the first therapeutic research study in pre-manifest HD. The principal investigators hope that this initial trial will lead to later trials that study the delay of onset of HD. The study is estimated to be completed by summer 2010.
Numerous studies conducted in the past decade show that coenzyme-Q10 may prove to be an effective drug in treating HD since it can enhance ATP production. Studies in the past have shown it to significantly delay HD symptoms and increase survival, especially in mice. However, side effects are still common, with gastrointestinal upset being the most common side effect in both human and animal trials. The PREQUEL clinical trial will study the effectiveness of coenzyme-Q10 in delaying the onset of HD in individuals who do not yet exhibit the symptoms of the disease. Overall, coenzyme-Q10 holds promise as a supplement to treat HD.
For further reading^
- Smith KM, Matson S, Matson WR, Cormier K, Del Signore SJ, Hagerty SW, Stack EC, Ryu H, Ferrante RJ. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington’s disease mice. Biochimica et Biophysica Acta 1762 (2006) 616–626.
This study demonstrates that larger doses of coenzyme-Q10 are more effective in treating HD mice. A fairly technical research article.
- Koroshetz, et al. “Energy Metabolism Defects in Huntington’s Disease and Effects of Coenzyme Q sub 10”. Annals of Neurology. 1997, Feb; 41(2): 160-5.
This study used oral supplements of coenzyme-Q10 to raise energy metabolism in nerve cells and lower lactate levels in human HD patients. A technical research article.
- The Huntington Study Group. “A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease.” Neurology. 2001, Aug 14; 57(3): 397-404.
This experiment indicates that the use of remacemide and CoQ10 was not efficient enough to warrant study as a treatment. A fairly technical research article.
- Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG,Hersch SM, Beal MF. “Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease.” The Journal of Neuroscience, March 1, 2002, 22(5):1592-1599
This article is the first study from the Ferrante group about treating mice with low doses of coenzyme-Q10. A technical article.
-A. Zhang, 6-8-10
While Huntington’s disease is traditionally thought of as a disease of the brain, its effects are much more widespread: many people with HD lose a dangerous amount of weight, complicating a disease that is already complicated enough. Although weight loss is one of the most serious non-neurological problems of HD, scientists don’t fully understand why it occurs. This medical mystery has driven scientists deep into the biology underlying weight loss in HD. Researchers have recently turned up a few potential explanations, and our increased understanding of this symptom is leading scientists to look at possible new ways of treating the disease.
Weight Loss in HD
People with HD tend to weigh less than those without the disease. A group of researchers from the Huntington Study Group followed 927 people with early-stage HD. For a description of the stages of HD, please click here. The investigators found that people with early-stage HD weighed an average of 10 kilograms (22 pounds) less than age-matched controls, which are people of the same age who don’t have the disease. Another study found that people with HD lose an average of 0.9 pounds per year, which stands in stark contrast to the average American, who gains 0.4-2 pounds yearly.
Unfortunately, while 0.9 pounds doesn’t seem like much, that’s just an average; some people with HD lose so much weight that their health is impacted. Weight loss worsens other aspects of the disease as underweight patients become malnourished and weak. Underweight patients are more susceptible to infection, and take longer to recover from illness, operations, and wounds. Weight loss also increases the likelihood of developing pressure ulcers, commonly known as bedsores, as bedridden patients have less fat tissue to cushion them from pressure. Patients who lose the most weight report a lower quality of life, and are more likely to feel apathetic and depressed. In the late stages of the disease, some patients lose so much weight that they need a feeding tube to stay healthy, as described here. On the other hand, people who start out heavier fare better; people who have a high body-mass index (BMI) when symptoms begin progress more slowly through the disease. Visit this website for an explanation of BMI and a for BMI calculator.
A Medical Mystery
While weight loss is one of the most serious non-neurological problems associated with HD, doctors don’t understand why it happens. Many suggestions have been put forth, but most of them have been disproved, forcing researchers to dig deeper to understand this phenomenon.
Doctors once believed that weight loss was due to chorea, the uncontrolled movements characteristic of HD. Doctors thought that people with HD lost weight because they burned extra energy as a result of the involuntary movements of chorea. However, three experiments indicate that chorea can’t be fully responsible for weight loss.
The first piece of evidence comes from looking at the early stages of the disease. People who have just been diagnosed with HD – and therefore have very mild symptoms – already weigh less than people without the disease. As mentioned earlier, people in early-stage HD weigh an average of 10 kg less than those who are not affected by the disease. Another group of researchers arrived at similar results; a study of 361 people with early-stage HD found that they have BMIs an average of 2 points lower than those without the disease, even if the patients had just been diagnosed with HD within that year and hadn’t yet begun to experience choreic movements. Researchers concluded that chorea alone could not explain why people with HD have lower BMIs, and that other factors are at play.
Other studies suggest that chorea may not have as much of an impact as doctors once thought. Pratley et al. measured how much movement chorea caused, in an attempt to quantify how much weight patients lose due to choreic movement. After measuring the movements of 17 people with mild to moderate HD for a week, they found that chorea caused people with HD to move more than people without the disease when sedentary: people with HD moved 14% more than people without HD while sitting or lying down. However, people with HD do less voluntary activity. Study participants with HD walked around and exercised less than people without the disease. In the end, Pratley et al. were surprised to discover that sedentary over-activity balanced out voluntary under-activity: people in the early and middle stages of HD don’t actually move more than people without the disease.
A similar study by the European Huntington’s Disease Initiative Study Group (EHDI) measured weight loss in 517 people with HD, and found no correlation between the amount of weight people lost and the severity of their motor symptoms; people with good scores on tests measuring motor symptoms (such as the UHDRS) were just as likely to lose weight as those with bad motor scores. For more information on diagnostic tests like the UHDRS, click here.
The final strike against the chorea theory comes from observations of people with late-stage HD. Weight loss is most drastic in the final stages of HD, despite the fact that chorea has usually ceased and patients are largely bedridden. So while chorea contributes to weight loss in HD, it cannot stand as the sole explanation.
Reduced Food Intake
Others suggest that people with HD lose weight because they have trouble eating; as the disease progresses, it becomes increasingly difficult to perform the complicated series of movements needed to eat, chew, and swallow.
However, this theory is also not enough to fully explain the weight loss. Studies have shown that people with HD actually tend to eat more than people without the disease; a study of 25 people with HD found that they ate an average of almost 400 calories more each day than people without the disease. Others report that they’ve had patients who eat up to 5000 calories a day – over twice the average daily caloric intake – just to maintain their weight.
So two popular explanations for weight loss in HD – chorea and insufficient diet – cannot entirely explain why people with HD lose so much weight.
Possible Biological Causes
Though the reasons for the mysterious weight loss are unclear, scientists are currently testing a few ideas.
Abnormalities in Energy Metabolism
One leading idea has to do with metabolism, the way the body burns calories to produce energy. HD researchers have long suspected that the disease-causing form of huntingtin (hereafter described as mutant huntingtin) interferes with energy metabolism, as described here. Results from a recent study suggest that this interference might contribute to weight loss.
After discovering that weight loss is not correlated with motor symptoms, scientists from the EHDI Study Group looked for other factors that might be to blame. They found that weight loss could be partially predicted by the number of CAG repeats on a patient’s copy of the mutant huntingtin gene; for every additional CAG repeat a patient had, they lost on average an extra 0.136 BMI points (0.8 pounds) over the course of the three year period that the study was conducted. For an explanation of CAG repeats, please click here.
The same holds true in mouse models of HD. The EHDI Study Group found that the more CAG repeats an HD mouse had, the more it tended to eat. Yet paradoxically, the mice with the most CAG repeats lost the most weight. So people and mice with more CAG repeats lose more weight.
The EHDI investigators suspect that this is due to the long tail of the mutant huntingtin protein. People with more CAG repeats produce mutant huntingtin with a longer tail, as described here. The EHDI investigators suggest that the mutant huntingtin protein interferes with the way cells make energy, and that longer-tailed proteins cause more problems. Mutant huntingtin has been shown to disrupt proteins that are needed to make energy and can damage mitochondria, the “energy factory” of our cells, as described here. In support of the theory that proteins with longer tails are more problematic, scientists at the MacDonald lab in Boston studied cells engineered to express mutant huntingtin. They found that cells with more CAG repeats made less ATP, the energy currency of the cell. So it seems possible that the more CAG repeats individuals have, the less efficient their cells are at converting calories to energy.
A second school of thought suggests that weight loss is due to hormonal disturbances in people with HD. Hormones are the body’s chemical messengers, and are important for regulating physiological processes, like hunger. The hypothalamus secretes many hormones, so when HD causes cells in the hypothalamus to malfunction and die, hormone production is disturbed.
Some of the hormonal signals that the hypothalamus sends out go to the gut and fat tissue, and direct processes like eating and burning energy – processes that are very important in maintaining a healthy weight. Therefore, some scientists think that cell death in the hypothalamus causes hormonal changes that might contribute to weight loss and other problems such as sleep disturbances, as described here.
Further insights have come from studying the way mutant huntingtin interacts with the digestive system. Certain symptoms of HD have hinted that the disease might affect the gut; apart from weight loss, people with HD often experience nutritional deficiencies, cramps, and wasting of skeletal muscles. People with HD are also prone to gastritis, a disease where the stomach lining becomes irritated or swollen.
Despite these symptoms, many HD researchers have traditionally thought that mutant huntingtin only affected the brain – a belief that struck some as strange because the protein is made and found throughout the body. However, results from a recent study suggest that mutant huntingtin in the gut might interfere with important digestive processes, thus contributing to weight loss.
In the study, van der Burg and colleagues looked at R6/2 mice, which are mouse models of HD described in greater detail here. They noticed several physiological changes that could all impact digestion. First, they noticed that the small intestines of HD mice were 10-15% shorter than those of normal mice, and that they had smaller villi, the tiny finger-like projections in the gut that take up nutrients. On top of that, scientists noticed that the mucus lining of the gut of the HD mice was 20-30% thinner. Since all of these structures are needed for nutrient absorption, these findings suggest that HD mice can’t take up nutrients as efficiently as normal mice.
Furthermore, the group found that the HD mice were missing a few key hormones that control the speed at which food passes through the body. This caused an increase in ‘transit time’: the food passed more slowly through the gut. Longer transit time might foster bacterial growth; if food takes longer to pass through the gut, harmful bacterial have more time and a better opportunity to flourish. This could make the small intestine irritated and inflamed, which could cause malabsorption of nutrients, chronic diarrhea, nausea, bloating, flatus, and weight loss. Those bacteria might also use up nutrients that the body would have otherwise taken up.
To see whether these physiological differences actually have an impact on digestion, researchers then compared the feces of HD mice to those of normal mice. They found that HD mice excreted more of what they ate, suggesting that they absorbed fewer calories and nutrients from their food. Notably, the mice that were the worst at absorbing nutrients from their food lost the most weight.
Van der Burg et al. had a few ideas as to what mutant huntingtin might be doing to interfere with digestion. Since the protein is present in gut cells, it could interfere with cell function and nutrient absorption. They also thought that mutant huntingtin might affect transcription, the process by which DNA is converted into protein as described here. If mutant huntingtin affects transcription in gut cells, it could cause a decrease in levels of important proteins needed for cells to survive and function properly.
While findings in HD mice don’t always translate to humans, these results indicate that scientists might benefit from studying the way HD affects digestion in people. Van der Burg et al. suggest that such research might help doctors improve their understanding of nutritional supplements for HD, and might even change the way we think about how people with HD metabolize and react to medicine.
Weight loss in HD has long puzzled doctors, patients, and caretakers alike. Two popular explanations of the phenomenon – chorea and reduced food intake – have been debunked as major contributors to weight loss. However, scientists have made new in-roads in recent years. By discovering that mutant huntingtin might disrupt energy metabolism, digestion, and hormones in HD mice, scientists have enhanced our understanding of HD, which may pave the way to new treatments and therapies. For example, the hypothesis that weight loss is linked to abnormalities in energy metabolism suggests that energy-boosting drugs – namely creatine and Coenzyme Q10 – are strong candidates to fight HD, as described in these articles here. Each further discovery about HD leads to a greater understanding of the disease, and brings hope for patients and families.
1. Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T; EHDI Study Group, Roos RA. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology. 2008 Nov 4;71(19):1506-13.
This medium-difficulty study describes how people with more CAG repeats lose more weight – and provides some theories as to why that might be the case.
This medium-difficulty article describes weight loss in people with early-stage HD
3. Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J; Huntington Study Group. Rate and correlates of weight change in Huntington’s disease. J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):209-12.
This medium-difficulty article describes weight loss in people with early-stage HD
4. Kremer HP, Roos RA. Weight loss in Huntington’s disease. Arch Neurol. 1992 Apr;49(4):349.
5. Petersén A, Björkqvist M. Hypothalamic-endocrine aspects in Huntington’s disease. Eur J Neurosci. 2006 Aug;24(4):961-7. Epub 2006 Aug 21. Review
This technical article describes how hormonal changes in people with HD might lead to weight loss
This easy-to-read handbook is a very helpful resource for caregivers taking care of people in late-stage HD
This study measured movements of people with HD, and found that their total energy expenditure was the same as that of people without the disease, and is somewhat technical
8. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 2005 Oct 1;14(19):2871-80. Epub 2005 Aug 22.
This technical article describes how huntingtin interferes with energy metabolism in a CAG-dependent fashion
9. Trejo A, Tarrats RM, Alonso ME, Boll MC, Ochoa A, Velásquez L. Assessment of the nutrition status of patients with Huntington’s disease. Nutrition. 2004 Feb;20(2):192-6.
This medium-difficulty paper discusses the result of the study on 25 HD patients that ate an average of 400 calories more than controls each day.
10. van der Burg JM, Winqvist A, Aziz NA, Maat-Schieman ML, Roos RA, Bates GP, Brundin P, Björkqvist M, Wierup N. Gastrointestinal dysfunction contributes to weight loss in Huntington’s disease mice. Neurobiol Dis. 2011 Oct;44(1):1-8. Epub 2011 May 23.
This technical article describes the impact of huntingtin on digestion in HD mice
M. Hedlin 11.16.11
What are clinical trials?
In order for any drug or treatment to be approved for human use by the FDA, it must first successfully pass clinical trials. A clinical trial is a medical or health-related research study in humans that follows a strict protocol in a carefully monitored, scientifically controlled setting. Clinical trials are generally conducted after a drug or treatment has shown promise in research studies using animal models.
What are the different types of clinical trials?
There are four main types of clinical trials: treatment trials, prevention trials, diagnostic trials, and screening trials.
- Treatment trials test the effects of new drugs, new combinations of drugs, or new procedures used to treat an illness or condition. Participants in this type of trial would already experience symptoms of HD and could be in any stage of HD.
- Prevention trials aim to prevent or delay onset of a disease in people who are at risk and test the effects of treatments that do so. Participants in this type of trial would be pre-symptomatic HD patients, usually people who have tested positive for the HD gene but have not yet exhibited any symptoms.
- Diagnostic trials are conducted to discover better procedures to diagnose an illness or disease.
- Screening trials are conducted to discover better ways to detect an illness or disease.
Diagnostic and screening trials are not needed to diagnose HD since current genetic tests can reliably and accurately identify HD. However, these types of trial design may be useful to research presymptomatic measures of HD disease progression and/or develop ways to better assess disease risk in the intermediate range where definitive genetic diagnosis is not currently possible. For more on genetic testing of HD, click here.
Clinical trials are conducted in phases.
- In Phase I trials, researchers first test a new treatment on a small group of individuals, typically 20-80 people, to evaluate its safety, determine a safe dosage range, and to identify side effects.
- Once the treatment passes Phase I trials, Phase II trials are conducted on more people, around 100-300 people, to see if it is effective and to further evaluate its safety and side effects.
- Once Phase II trials are completed successfully, the drug moves onto Phase III trials, in which researchers confirm the drug’s effectiveness, monitor any side effects, compare it to standard treatments, and collect information that will allow the experimental drug or treatment to be used safely long-term.
- Only after the drug or treatment has passed all phases will it be approved by the government.
All clinical trials have criteria specifying who can or cannot participate. There are many risks and benefits to participating in a clinical trial. For example, participants contribute to medical research, have access to medical care, and if assigned to the treatment group, are given new potential treatments throughout the trial. However, participants may also experience negative side effects as a result of participating, or they may receive a placebo. Clinical trials must follow strict ethical codes and are highly regulated to ensure the safety of participants as much as possible.
What is the Huntington Study Group?
The Huntington Study Group (HSG) is an international non-profit group whose aim is to support clinical research of Huntington’s disease (HD). It was formed in 1993 and has members and research sites in the US, Canada, Europe, Australia, New Zealand and South America. The HSG often partners with pharmaceutical companies, private foundations, and government agencies to fund research investigating the effects and safety of HD interventions. (For more information on the HSG, click here).
Ongoing Studies that are Currently Enrolling Participants
2CARE is a phase III trial that aims to study coenzyme-Q10 as a potential treatment for HD. For more on coenzyme-q10, click here. The study aims to measure the effectiveness of coenzyme q-10 in slowing the symptoms of HD and to study the long-term safety of administering the compound to people with HD. Previous studies have shown that coenzyme q-10 slightly slowed the progression of HD, but not enough to yield significant results. Compared to these previous studies, 2CARE uses a much higher dosage for a longer time period. To date, it will be the largest therapeutic clinical trial of HD, with expected enrollment of over 600 in the United States, Canada, and Australia. The study began in March of 2008 and is expected to be completed by April 2014. 2CARE is a double blind placebo study, in which participants are randomly assigned to one of two groups. The experimental treatment group will receive oral administration of coenzyme q10 in chewable form twice a day, for a total of 2400 mg/day. In a preliminary study called Pre2CARE, dosages ranging from 1200 to 3600 mg/day were tested; 2400 mg/day appeared to be the most effective dosage, as smaller dosages were not as effective, and larger dosages resulted in the mildly unpleasant side effect of upset stomach. Researchers will compare total function capacity (TFC) scores, tolerability, adverse events, vital signs, and laboratory test results between the two groups.
The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester are currently conducting a phase III clinical trial to assess the effects of creatine supplements on slowing the progression of symptoms in HD patients. Creatine is a molecule naturally produced in the body and consumed in the diet, found mostly in meat. Previous studies conducted on transgenic mouse models have shown that mice supplemented with creatine displayed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. The study is called the Creatine, Safety, Tolerability, & Efficacy in Huntington’s disease (CREST-E). Participants are randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study is a fairly large clinical trial. It will involve 44 research centers from around the world and enroll up to 650 participants. The study will last 37 months and is estimated to be completed in December of 2014. (For the most updated information on this study, click here).
Earlier in 2009, the HSG received funding from the NIH to test the safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not yet show any motor symptoms. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials) and is a phase II trial. The study will be conducted at 10 clinical sites throughout the nation and is the first therapeutic research study in pre-manifest HD patients. Participants will be randomly assigned to experimental groups receiving 600, 1200, and 2400 mg/day of coenzyme q10. The principal investigators hope that this initial trial will lead to later trials that study the delay of HD.
Ongoing Studies that are No Longer Enrolling Participants
ACR16 is a dopamine stabilizer and can enhance or inhibit dopamine controlled functions. For more information on the role dopamine plays in HD, click here. The HSG is conducting a phase II clinical trial testing different doses of ACR16 on HD patients age 30 and older. HART is sponsored by NeuroSearch Sweden AB, a biopharmaceutical company, and is being conducted in 35 research sites across North America. Previous studies showed that ACR16 is safe and tolerable in patients with HD and Parkinson’s disease. Additionally, it has been shown to significantly improve patients’ voluntary and involuntary movements. Participants are randomly assigned to one of four groups-three experimental groups given different doses of ACR16 and a placebo group. The study occurs over a course of 12 weeks. As of October 2010, results have been promising, as patients in the highest dosage group (90 mg/day) displayed significant improvement in motor function as measured by the modified Motor Score (mMS).
Recently Completed Clinical Trials
HORIZON was a phase III clinical trial conducted by the HSG and the European Huntington’s Disease Network that investigated whether dimebon is safe and effective in improving cognitive abilities in patients with HD. Dimebon is an experimental drug that has been shown to prevent the death of brain cells in animal models and is currently being tested to treat HD and Alzheimer’s Disease. It is thought to work by stabilizing and improving function of the mitochondria. For more information on dimebon, click here. The study was conducted in various centers in the United States, Canada, Europe, and Australia. It was a double-blind, placebo study in which participants were either given 60 mg of Dimebon daily or a placebo. Results showed that dimebon is not effective in treating HD. There was no statistically significant difference in symptoms between the experimental and placebo groups. According to the president and chief executive officer of Medivation, development of dimebon in HD will be discontinued.
Minocycline is an antibiotic that is primarily used to treat acne and other skin disorders. For more on minocycline, click here. The goal of DOMINO was to assess whether minocycline was safe and effective in slowing HD progression and whether further studies should be conducted. The study is a phase II clinical trial that was started in 2006 and completed in November 2008 by the HSG with funding by the FDA Office of Orphan Products Development. It was a double-blind, placebo experiment in which participants were randomly assigned to a treatment group that received 100mg of minocycline twice daily or a placebo. The TFC scores of the two groups were then compared. Results showed that while minocycline was safely tolerated, it did not produce a significant effect in terms of delaying HD symptoms, and thus, further study of minocycline in treating HD is not warranted.
TREND-HD was a large phase III trial that began in September 2005 and was completed in August 2007. The goal of the study was to determine whether ethyl-EPA (Miraxion) slowed the progression of motor decline in HD patients. Ethyl-EPA is an omega-3 fatty acid commonly found in fish oil. Study participants had mild to moderate HD, meaning they displayed early signs of HD but were self-sufficient in daily living activities. For the first 6 months, the treatment group received ethyl-EPA while the placebo group received a placebo. For the next 6 months of the study, the placebo group was also given the active drug. Interestingly, there were no significant differences in Total Motor Scores between the two groups after the first 6 months of the placebo study. However, after the next 6 months in which all participants received the drug, the experimental group showed improvement as compared to the group that had initially received the placebo for the first 6 months. Further studies will need to be conducted to determine the efficacy of ethyl-EPA. There did not appear to be any safety concerns. After the study was completed, the investigators and sponsor of the study, Amarin Neuroscience Ltd., took the unprecedented step of telling the study participants about the results of the study by calling them and inviting them to a telephone conference regarding the study results. Study participants are typically not informed of the results of the clinical trials they participated in.
Huntington Study Group (HSG) and Prestwick Pharmaceuticals collaborated on a clinical trial. Called TETRA-HD involving tetrabenazine, a dopamine depletor. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD was a phase III clinical trial with the goal of determining the optimal dosage of tetrabenazine in treating chorea in people with HD. The trial was carried out at 16 different HSG sites in the United States, involving a total of 84 participants with HD. Fifty-four of the participants were randomly assigned to receive tetrabenazine for 12 weeks with increasing dosages over the first 7 weeks. The other 30 served as the comparison group and received a placebo. The results of the study indicated that tetrabenazine is effective in treating chorea with side effects that are less severe than those associated with other anti-choreic drugs. On the CGI Global Improvement Scale, 6.9% of the patients receiving placebo had more than minimal improvement compared to 45.1% of the patients receiving tetrabenazine. Clinical assessments showed that tetrabenazine was associated with drowsiness and insomnia in four patients, depressed mood in two, parkinsonism in two and akathisia in two. Most cases of adverse effects improved after adjusting dosage levels, but the risk of side effects should be considered. These results confirm the benefits of tetrabenazine usage in ameliorating the symptoms of chorea. In August 2008, the FDA approved tetrabenazine as the first drug for treatment of chorea, and it is used worldwide today.
For more information:
-A. Zhang, 7-5-11
Drug Summary: Remacemide (RMC) is a drug that HD researchers hope can alleviate glutamate toxicity in the brains of HD patients. Remacemide is an NMDA antagonist – it inhibits the binding of glutamate to NMDA receptors, preventing glutamate from exerting its toxic effects on the nerve cell. Although, it has been shown to transiently improve motor performance in mouse models of HD, the few human clinical trials that have been performed have not produced statistically significant improvements in brain or motor function. Patients have also experienced side effects such as lightheadedness, dizziness, vomiting, nausea, and gastrointestinal disturbance.
The lowered amount of energy available in the nerve cells of patients with HD is thought to cause NMDA receptors to be oversensitive to glutamate. Therefore, normal physiological levels of glutamate can cause overexcitation of the NMDA receptor, leading to the influx of calcium ions into the cell. Excess calcium ion entry can lead to cell death through a combination of events. (For more information, click here.)
Remacemide, sometimes referred to as Remacemide Hydrochloride, is under investigation as a treatment for HD because it acts as a non-competitive inhibitor of the NMDA receptor. This means that remacemide decreases the receptor’s ability to bind glutamate by docking to a site on the receptor other than the glutamate binding site, and changing the shape of the receptor such that glutamate has a difficult time binding. Researchers hope that by inhibiting the NMDA receptor, the toxic effects of glutamate in the neurons of patients with HD can be lessened.
Clinical trials have examined the effectiveness of remacemide in curbing or stopping the neurodegenerative effects of HD in humans. Although remacemide treatment has not produced statistically significant improvement in these trials, in some patients it seems to transiently improve certain motor symptoms caused by HD such as chorea. Side effects such as dizziness, nausea, vomiting, lightheadedness, and gastrointestinal disturbances tended to accompany treatment.
Experiments done on mouse models of HD have been more positive.
Research on Remacemide
Kieburtz, et al. (1996) conducted a study on the effects of remacemide in 31 participants in the early-stages of HD. The study was conducted over a 5-week period and the participants were divided into three treatment groups:
The total functional capacity (TFC) of the participants was used as the criteria of the drug’s effectiveness. TFC is a standardized scale used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The TFC scale ranges from 13 (normal) to 0 (severe disability). The HD Motor Rating Scale (HDMRS) was also used to assess the motor capabilities of the participants. The HDMRS consists of 14 items that assess the relevant motor features of HD including chorea and other motor functions. Other psychological tests were also conducted to measure the effectiveness of the drug in improving cognitive function.
Following treatment, the researchers concluded that there was no statistically significant difference between the three treatment groups. However, a trend towards improvement in chorea was observed among the participants who received 200 mg of remacemide per day. No major side effects were observed in most of the participants. However, one of the participants who received 600 mg/day did not complete the study due to persistent nausea and vomiting, which was believed to be a result of the medication.
The researchers concluded that remacemide could have short-term effects in improving chorea experienced by people in the early stages of HD. No statistically significant changes in cognitive performances were seen in the treatment groups. Larger, long-term controlled studies of remacemide are needed to determine the duration of tolerability and potential benefits of remacemide and other NMDA blockers.
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at 23 sites in the United States and Canada, monitored between July 1997 and June 1998. Participants in the study were assigned to four different treatments:
The primary measure of the drug’s effectiveness was change in total functional capacity (TFC) of the people with HD. A score of 13 represents a normal degree of function and a score of 0 represents a severely disabled state. The average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC.
The condition of the participants who were treated with remacemide worsened by 2.3 points on the TFC scale, showing that the drug had no beneficial effect on slowing the functional decline experienced by people with HD. However, there was a trend toward an improvement in the degree of chorea in the participants treated with remacemide. Although this effect was not statistically significant, the effect was seen during the patient’s first visit after treatment began, suggesting that remacemide may decrease chorea. These findings suggest that antiglutamate therapies could be useful in controlling chorea even if they have no impact on slowing functional decline. However, remacemide was associated with side effects that included dizziness, lightheadedness and nausea. A trend towards a decrease in TFC decline was seen in the participants treated with CoQ10. (For information on CoQ10, click here.)
Ferrante et al. (2002) studied the potential therapeutic effects of remacemide, coenzyme Q10, and the combination of the two drugs on transgenic mouse models of Huntington’s Disease. They found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using CoQ10 and remacemide together, was even more effective than either compound alone.
For further reading
- Kieburtz, et al. “A controlled trial of remacemide hydrochloride in Huntington’s disease.” Movement Disorders. 1996, May; 11(3): 273-7.
This article contains the full details on the study by Kieburtz, et al.
- The Huntington Study Group. “A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease.” Neurology. 2001, Aug 14; 57(3): 397-404.
This article contains details on the study done by The Huntington Study Group.
- Schilling, et al. “Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model.” Neuroscience Letters. 2001, Nov 27; 315(3): 149-153.
- Ferrante, et al. “Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington’s Disease.” Journal of Neurosience. 2002, Mar 1; 22(5): 1592-1598.
-P. Chang, 7/5/04More
Drug Summary: Nicotinamide (also referred to as Vitamin B3) is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide), an important molecule involved in energy metabolism. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Nicotinamide has been shown to be effective at curing motor symptoms in a mouse model of HD.
Nicotinamide and Energy Metabolism
Nicotinamide is a vitamin that plays an important role in the synthesis of components necessary for the production of ATP. A more familiar term for nicotinamide is Vitamin B3. Vitamin B3 can be found in various meats, peanuts, and sunflower seeds. Nicotinamide is the biologically active form of niacin (also known as nicotinic acid). Both nicotinamide and nicotinic acid, as well as a variation on nicotinic acid, called inosital hexaniacinate, are available as supplements.
The human body receives its necessary quantities of nicotinamide from two sources: diet, as described above, and by synthesizing nictonamide in the body itself. Our body is able to convert tryptophan, an amino acid regularly found in the body, into niacin. Niacin is then converted to nicotinamide, which the body uses for various purposes. Figure J-2 shows a diagram depicting how nicotinamide is produced in the body.
Nicotinamide is sometimes preferred as a supplement because it lacks some of the side effects of niacin. Niacin, but not nicotinamide, has been used as a drug to lower blood cholesterol levels. Nicotinamide, on the other hand, has been found to be effective in arthritis and early-onset Type I diabetes. Nicotinamide is also currently being studied for its effects in improving energy deficits caused by mitochondrial dysfunctions.
Various diseases such as Huntington’s disease, Parkinson’s disease, and mitochondrial disorders are associated with impaired energy metabolism due to various mitochondrial dysfunctions. Nicotinamide is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide) which is an important molecule involved in energy metabolism. NAD acts as an electron carrier, meaning that it can accept and donate electrons to various enzymes involved in energy metabolism. Specifically, NAD is transformed into NADH when it accepts electrons in a number of reactions involved in glycolysis and the Kreb’s cycle (steps in energy metabolism). NADH then donates its electron to complex I of the electron transport chain. For each pair of electrons passed along the electron transport chain from NADH, a number of ATP molecules are formed. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Figure J-3 shows an image tracing the role of NAD in the cell.
Nicotinamide can also increase cellular energy by inhibiting the enzyme poly-ADP-ribose polymerase. Under normal conditions, damage to DNA activates poly-ADP-ribose polymerase. When poly-ADP-ribose polymerase is activated, it depletes the supply of NAD by transferring poly-ADP-ribose subunits from NAD to various DNA repair enzymes. The depletion of NAD leads to the depletion of ATP due to the decrease in the activity of both glycolysis and the Kreb’s Cycle. When nicotinamide inhibits the poly-ADP ribose polymerase, it essentially prevents the NAD molecules from becoming depleted.
Relationship between Nicotinamide and Nicotine
Nicotinamide was one of the first vitamins ever discovered. Around the same time that it was discovered, scientists also found that nicotine, the addictive substance in tobacco products, can be harmful to humans. One of the ways by which nicotine causes deterimental effects in humans is that it has a similar structure to nicotinamide and can interfere with the absorption and incorporation of the vitamin. Figure J-4 shows the structures of nicotinamide and nicotine.
Nicotine competes with nicotinamide for the binding sites in the enzymes needed for the absorption of nicotinamide, thereby lowering the amounts of nicotinamide available to cells. Figure J-5 shows a diagram depicting the competition between nicotinamide and nicotine. This competition results in the depletion of NAD molecules that the cell needs to produce energy. This is one of the reasons why smoking can worsen the condition of people with mitochondrial dysfunction.
Research on Nicotinamide
Beal, et al. (1994) examined whether Coenzyme Q10, nicotinamide, or riboflavin can block brain lesions produced by a compound that causes a dysfunction in the mitochondria. Coenzyme Q10, also known as ubiquinone, is an antioxidant and an essential component of the electron transport chain. (For more on Coenzyme Q10, click here.) Riboflavin is a precursor of another coenzyme needed by the electron transport chain. (For more on Riboflavin, click here.)
The researchers administered the mitochondrial toxin, malonate, to a group of male rats. Malonate acts as an inhibitor of complex II of the electron transport chain and has been known to disrupt oxidative phosphorylation, leading to lowered ATP concentrations. Administration of malonate has been known to cause lesions in brains due to the deficit in energy.
The measures used by the researchers to assess the efficacy of the various supplements were lesion size after malonate administration and ATP concentrations. The researchers discovered that rats treated with coenzyme Q10 alone or nicotinamide alone showed decreased lesion size, while treatment with riboflavin had no effect on lesion size. Mice treated with a combination of coenzyme Q10 and nicotinamide showed the greatest reduction in lesion size. Furthermore, the combination of coenzyme Q10 and nicotinamide increased ATP concentrations and prevented ATP depletion caused by malonate.
These results suggest that coenzyme Q10 and nicotinamide can block ATP depletions and may improve the efficiency of the electron transport chain. It is therefore possible that coenzyme Q10 and/or nicotinamide may be able to slow the progression of HD, given that inefficiency of the electron transport chain contributes to the progression of HD.
Schulz, et al. (1995) studied the potential neuroprotective effects of Coenzyme Q10 and nicotinamide on mouse models of Parkinson’s disease (PD). Impaired energy metabolism has been found to be associated with some of the symptoms of PD.
To mimic the symptoms seen in people with PD, the researchers administered MPTP, a poison that is toxic to nerve cells. Administration of MPTP disrupts the energy metabolism of cells that release the neurotransmitter dopamine. Specifically, MPTP administration results in an inhibition of complex I of the electron transport chain of dopamine-releasing nerve cells. The impairment in the electron transport chain results in decreased ATP and increased lactate levels in the brains of people with PD. The affected dopamine cells are also unable to release as much glutamate, resulting in decreased dopamine levels in people with PD.
The researchers divided the mice into two groups – one group was given water that contained MPTP while another group was given normal water. The mice were then treated with either coenzyme Q10 alone, nicotinamide alone, or a combination of coenzyme Q10 and nicotinamide. They found that in mild cases, the combination of coenzyme Q10 and nicotinamide significantly protected neurons, lowering the rate of dopamine depletion. However, treatment was ineffective in mice with more severe dopamine depletions. Nicotinamide alone produced significant neuroprotective effects and prevented dopamine depletion in mild cases, but coenzyme Q10 alone showed no significant effect.
Hathorn et al. (2011): Scientists studied nicotinamide in a mouse model of Huntington’s disease. They used R6/1 mice that had between 122 and 127 CAG repeats. Each mouse given a dose based on its weight; for every gram that a mouse weighed, it received 250 micrograms of nicotinamide a day. Mice began treatment when they were 8 weeks old, and treatment ended when they were 20 weeks old.
The mice were measured in two ways. First, the behavior of the mice was studied once every two weeks. Scientists found that HD mice treated with nicotinamide were much better at tasks that required motor skills than untreated HD mice. They also found that treated HD mice explored their cages just as much as mice that didn’t have the HD mutation – which is important because HD mice generally move around much less than healthy mice.
Scientists also studied the brains of the mice. They found that levels of BDNF, an important chemical in the brain that promotes neuron health, were restored to normal. There were also increased levels of PGC-1a, a chemical that is involved in energy metabolism in the cell. However, nicotinamide did not decrease protein aggregates, or prevent the late-stage weight loss that HD mice and patients with HD generally experience. The scientists suggested that nicotinamide could be a useful treatment when used in combination with other treatments that reduce protein aggregation and help fight weight loss.
For further reading
- Beal, et al. “Coenzyme Q10, and Nicotinamide Block Striatal Lesions Produced by the Mitochondrial Toxin Malonate.” Annals of Neurology. 1994; 36(6): 882-88.
This article reports that nicotinamide treatment was able to improve the conditions of cells exposed to a mitochondrial toxin.
- Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This technical article describes the study in which HD mice are treated with nicotinamide.
- Schulz, et al. “Coenzyme Q10 and Nicotinamide and a Free Radical Spin Trap Protect against MPTP Neurotoxicity.” Experimental Neurology. 1995; 132: 279-283.
This article reported that nicotinamide treatment improved the condition of mouse models of Parkinson’s Disease.
- Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This study found that nicotinamide helped relieve symptoms in a mouse model of HD, and is fairly technical
- Vitamin B-3: Niacin. Online.
This web page describes food sources, benefits, recommended daily allowances, as well as warnings and precautions with regards to supplementation.
-E. Tan, 9-22-01; Updated by P. Chang, 5-6-03, updated by M. Hedlin 7-20-11More
Readers of our website sometimes ask, “Where does all the research summarized by HOPES come from?” Here follows a list of some main contributors to HD research, along with some of their recent studies, clustered in five categories:
We’ve also included some news articles highlighting the key discoveries. You will notice that the “Recommended Reading” list at the end draws directly from medical journals, so please be forewarned: the material there may be complex.
Biological Basis of HD
Johns Hopkins University School of Medicine
Director: Christopher A. Ross, M.D., Ph.D.
- Discovered a gene that, when mutated, causes a disorder called “Huntington’s disease-like 2,” or HDL2, which is very similar to HD.
- Found a way to make the CREB binding protein (a protein involved in the neuronal effects of HD) harmless by cutting out certain molecular areas.
- Determined that HD causes movement abnormalities by preventing the basal ganglia in the brain from correcting its mistakes.
Representative News Article:
University of California, Irvine
- Found that a certain protein called arfaptin 2 can prevent the huntingtin protein from aggregating, although it is still unclear whether or not these aggregates cause HD.
- Discovered that a class of drugs called “histone deacetylase inhibitors” can actually prevent, and in some cases reverse, brain cell death in fruit flies.
Representative News Article:
Weill College of Medicine at Cornell University
- Used metabolism studies to show that mice who have the HD allele do not use energy as efficiently as normal mice do.
University of Pennsylvania School of Medicine
- Used fruit flies to show that certain protein chaperones may suppress HD.
- First to discover that HD causes proteins to aggregate in the brain.
- Found that huntingtin aggregates cause proteasomes to malfunction, which creates problems when toxic proteins collect.
- For more information about research at Stanford, click here.
- Researched why mutant proteins cannot be degraded in patients with HD.
Indiana University School of Medicine
- Sends researchers to Lake Maracaibo, Venezuela, a community that has a high number of related individuals who are predisposed to developing HD. Researchers obtain specimen samples and test neurological functions to determine the genetic inheritance of HD.
University of Southern California
- Studied the Lake Maracaibo community and found that HD is caused by many genetic mutations that happen during mitosis—not just one in meiosis—and that the number of CAG repeats on the HD allele increases as the mutations accumulate over time.
Massachusetts General Hospital
- Found that certain types of brain cells tend to appear in higher densities in people who have a family history of HD.
- Studied the effects of HD on the transcription of genes across generations.
The Search for Treatments
Massachusetts General Hospital
- Tested coenzyme Q10 as a potential treatment for HD, and found that the drug can extend patients’ lives and delay the onset of symptoms.
- Performed an inconclusive clinical trial of riluzole, a drug that had been shown to improve motor abnormalities in HD-afflicted baboons. Investigations of riluzole continue.
National Institutes of Aging (NIA)
- Recently found that periods of fasting decreased the symptoms of HD in mice. Low-calorie diets and reduced meal frequency can both delay the onset of HD and slow down the spread of the disease.
University of South Florida Center for Aging and Brain Repair
- Found that people whose diets are rich in antioxidants age slower because antioxidants block the free radicals that cause body function to decline.
- Successfully slowed aging in the brain by implanting stem cells from human umbilical cord blood.
- Discovered that when fetal tissue is implanted in the brains of HD patients, the new tissue remains free of HD.
- Challenged the relationship between protein aggregates and HD with the discovery that drugs such as cystamine can reduce the symptoms of HD without affecting aggregates.
Weill College of Medicine at Cornell University
- Conducted key research on potential HD treatments such as coenzyme Q10 and creatine.
Columbia Health Science HDSA Center for Excellence at the New York State Psychiatric Institute
- Found that HD patients’ grasping abilities decrease more and more over time.
- Studied a group of HD patients and found that over half of them had symptoms of obsessive-compulsive disorder.
- Currently exploring the safety of creatine for the treatment of HD.
Indiana University School of Medicine
- Recruited patients with a family history of HD and found that the ones who eventually developed the disease became more irritable and hostile before any other signs of HD appeared.
Johns Hopkins University School of Medicine
- Most HD patients also suffer from depression, impaired thinking, personality changes, and other disorders that can be treated with medication.
University of Connecticut Medical School
- Found that when HD patients are asked to do a cognitive task (like solving a word puzzle, for instance), less blood flows through their brains than through the brains of people who don’t have the disease.
University of Pennsylvania School of Medicine
- Found that HD patients are less able to identify odors than people who do not have HD.
Link to Publication:
Huntington Study Group (HSG)
HSG is a worldwide collaboration of researchers and physicians who work together to study HD. The group has produced numerous studies in the past; current projects include:
- MINO-HD: Aims to determine exactly how the drug minocycline affects HD patients. There is already evidence suggesting that the drug has positive effects, since minocycline prevents the expression of caspase, an enzyme that triggers certain events that lead to cell death.
- Prospective Huntington At Risk Observational Study (PHAROS): Plans to monitor people who are genetically at-risk for developing HD and to try and determine the circumstances under which these people actually go on to develop the disease.
- PREDICT-HD: Compares the brains of HD patients with those who are “at-risk” for HD to find out what triggers the disease. The difference between this study and PHAROS is that PREDICT-HD is recruiting patients who already know that they have the HD allele, whereas volunteers for PHAROS cannot know whether or not they have the mutation.
University of Rochester School of Medicine and Dentistry
- Researched the rate at which HD patients’ motor skills decline.
- Developed a method to test the reliability of diagnosing HD.
For Further Reading:
- Albin RL. Fetal striatal transplantation in Huntington’s disease: time for a pause. Journal of Neurology, Neurosurgery, Psychiatry. 2002 Dec; 73(6):612.
- Bonini NM. Chaperoning brain degradation. Proceedings of the National Academy of Sciences. Dec 10;99 Suppl 4:16407-11.
- Cattaneo E, Rigamonti D, Zuccato C. The enigma of Huntington’s disease. Scientific American. 2002 Dec; 287(6): 92-7.
- Kieburtz K. Issues in transplantation for Huntington’s disease. Cell Transplantation. 1999 July/Aug;8:456-457.
- McMurray CT. Huntington’s disease: new hope for therapeutics. Trends in Neuroscience. 2001 Nov;24(11 Suppl):S32-8.
- Parker M, Lucassen A. Working towards ethical management of genetic testing. Lancet. 2002 Nov 23;360(9346):1685-8.
- Sharma N, Standaert DG. Inherited movement disorders. Neurological Clinician. 2002 Aug;20(3): 759-78.
In July 2008, HOPES researcher Tiffany Wang visited the Huntington’s Disease Society of America Center of Excellence located at the Hennepin County Medical Center (HCMC) in Minneapolis, Minnesota. The Center of Excellence serves approximately four hundred Huntington’s Disease (HD) patients and families from Minnesota, North Dakota, South Dakota, Northern Iowa and Western Wisconsin. Although it was not formally designated as a Center of Excellence at its start, the HD clinic at HCMC has provided care to HD patients since it was founded in 1978. For more about HDSA Centers of Excellence please click here. Today, under the direction of Medical Director and neurologist Dr. Martha Nance, the HD clinic continues to provide patient care through an expanded program. The clinic is staffed by a multidisciplinary team of specialists, some of whom have worked with the HD clinic for over a decade. HOPES had the opportunity to speak with several of the staff members:
- Susan Braun-Johnson, P.T. Physical Therapist
- Sally Gorski, M.A. Speech-Language Pathologist
- Carol Ludowese, M.S. Genetic Counselor
- Mary Morgan LaGorio O.T.R. Occupational Therapist
- Stacey Payerl, R.D. Clinical Dietician
- Dawn Radtke, R.N. Clinical Research Coordinator
- Lena Ross, M.S.W. Social Worker
- David Tupper, Ph.D. Neuropsychologist
The HCMC Huntington’s Disease clinic is located in the Center’s Neurology department and provides patient care through weekly in-house admittance, monthly HD clinics and visits to long-term care facilities. Some of the clinic’s HD patients represent families that have been with the HCMC clinic for three generations. Generational patient care facilitates strong understanding of patient histories and good patient-physician relations.
Every Wednesday, neurologists Dr. Martha Nance and Dr. Scott Bundlie provide care to HD patients through in-house admittance at the medical center. These appointments with the neurologists are generally for newly diagnosed HD patients, genetic testing consultations and medication changes.
Patients who require other services are advised to visit the clinic during the monthly HD clinic days which occur one Wednesday per month. On these days, a multidisciplinary team of specialists offers services including consultations in neurology, physical therapy, speech-language pathology, genetic counseling, occupational therapy, nutrition, neuropsychology, and social services. Dr. Nance lauds the clinic days as being particularly helpful because patients and their families can see several different physicians and specialists without the hassle of scheduling several appointments or coming to the hospital for multiple visits. HOPES members were able to visit Minneapolis on one of the HD clinic days to see how they are run.
Before the HD clinic opens, the staff holds a meeting to determine the needs of incoming patients. Dr. Nance reviews relevant medical history and highlights concerns that may arise for each of the approximately ten patients who visit on clinic days. By holding the pre-clinic meeting, the staff members are prepared for more meaningful interactions with patients. Following the meeting, the specialists disperse to tend to the patients. Dr. Nance greets most patients personally, inquiring about how the patient has been since his or her last visit. Check-ups for the HD patients are usually scheduled for every three months, so most patients have news to tell Dr. Nance whether it is about serious new symptoms or simply a recent family vacation.
In many instances, the patient’s family and caregivers will accompany them to the clinic and can give insight into how the patient is coping with HD. Family members, particularly siblings and children of HD patients, may want to consider genetic testing. Genetic counselor Carol Ludowese talks with family members about their options for genetic testing. She can also give advice to younger family members about options like pre-implantation genetic diagnosis that would enable them to have children without passing on the genes for HD. For more information about genetic testing click here.
Following each of her consultations, Dr. Nance will report back to the rest of the HD clinic team who will go into the rooms to see the patients. The other specialists will then tailor visits and consultations to the needs of the patients and their families. In addition to finding out how the patients are doing holistically, Dr. Nance also asks more specific questions depending on the condition of the patient. Many of these questions are about topics that can be more thoroughly addressed by one of the specialists on the team.
Dr. Nance often asks about the patient’s weight and eating habits. One of the common symptoms of HD is weight loss, and in the later stages of the disease patients’ weights can fall significantly below healthy levels. If patients are showing drastic weight loss clinical dietician Stacey Payerl offers advice on how to maintain a healthy weight. Her recommendations often extend beyond what kinds of foods to eat to how caregivers can encourage food intake by making eating more enjoyable for the patient.
Speech-language pathologist Sally Gorski can also help patients who are having trouble maintaining a healthy weight. Patients find swallowing becomes more difficult as HD progresses, so she can administer a swallow exam to determine what kinds of foods are safe for a patient to eat without choking. To increase calorie intake and overcome swallowing difficulties, physicians often recommend that a feeding tube be inserted into the stomach. Dr. Nance emphasizes that whether or not a patient wants to have a feeding tube is an important issue to discuss early on because when the time comes to make the decision, the progression of HD may make it too difficult for patients to make the decision or convey their wishes to their families. Gorski can help patients and their families learn more information to help decide whether a feeding tube is right for them. Making the decision to have a feeding tube falls under the category of advanced directives, which Dr. Nance thinks are important to bring up to patients even during beginning stages of the disease.
While engaging the patients and families in conversation, Dr. Nance often asks patients to complete several motor tasks. Some of these actions include sticking the tongue out, walking a short distance, tapping the index and middle fingers against the thumb, and looking in different directions without moving the head. Watching the patients’ performances helps Dr. Nance evaluate which stage of HD they are in according to the Unified Huntington’s Disease Rating Scale (UHDRS). Physical therapist Susan Braun-Johnson and occupational therapist Mary Morgan LaGorio can provide more extensive advice to patients about their physical and motor symptoms, as well as ways to cope with these symptoms. For example, assistive devices can help in daily activity and changes within the home, such as installing additional bathroom equipment, can maximize safety. For more information about assistive devices and physical therapy click here.
Patients are also asked about their mental status and, if they are still formally employed, whether they are experiencing any difficulties at the workplace. These questions can help determine how behavioral and cognitive symptoms are progressing. If more thorough examination is needed, neuropsychologist Dr. David Tupper can administer several neuropsychological tests to determine how a patient’s brain is functioning. Results from these tests not only help members of the HD clinic better understand their patients, but they can also be important for determining qualifications for social security disability.
Questions about disability determination and other topics related to social services can be answered by the social worker Lena Ross on the HD clinic team. She can advise HD patients about resources within the community. One of the recurring topics that Lena receives questions about is health insurance. Given the complex nature of health insurance, patients along with families and caregivers often find it difficult to understand how HD patients can manage their healthcare costs. Lena can also answer questions regarding care for the patients who are progressing into the later stages of HD. Many family members of HD patients find it difficult to balance their busy lives with caring for a loved one with HD. It is important for families to recognize that HD patients can receive meticulous care without becoming a burden for their family at home. If a patient begins showing more severe symptoms, it may be safer to consider other options, such as a long term care facility. In this regard, Lena helps HD families learn about and weigh the options that are available to them.
At the end of the day, the HD clinic team meets again to discuss the status of the patients. Many patients are scheduled for another visit in three months or, if necessary, follow-up visits within a shorter amount of time. Although official reports are documented for each patient, the post-clinic session helps the HD clinic staff familiarize themselves with the patients for more individualized care.
For patients who are in the later stages of HD and cannot go to the clinic in Minneapolis, staff from the clinic visit local long-term care facilities to provide care to HD patients. The HCMC Center of Excellence is affiliated with the Good Samaritan Society – University Specialty Center also located in Minneapolis. The facility provides long-term care to patients with several chronic diseases and has a unit for HD patients that can care for up to fifty patients. Dr. Nance organizes monthly visits to the Good Samaritan Society patients. Whether at the HCMC or the Good Samaritan Society facilities, the HD clinic continues to provide comprehensive and personal care to its patients.
Dawn Radtke, Clinical Research Coordinator, spoke with HOPES about the research that is conducted at the HCMC Center of Excellence in Minneapolis. The Center has been directly involved with several clinical studies including some drug trials. Although the clinic is not engaged in HD research on the molecular level, the HCMC is affiliated with the University of Minnesota where many groups are researching HD-related biological mechanisms. Several factors are considered when the clinic chooses which studies in which to participate: time involvement for participants and medical staff as well as whether the clinic has an appropriate patient population for the study. Research is mainly focused on relieving the symptoms of HD.
From Ms. Radtke’s experience with patients, families and caregivers are responsive to the idea of participating in clinical trials. Most HD patients are eager to take part in drug studies because receiving a new drug that is not yet FDA approved may alleviate symptoms. Patients are warned, however, that they may receive a placebo rather than the new drug itself.
HCMC researchers face several challenges when conducting clinical trials. Ms. Radtke tells HOPES that the greatest challenge in managing research at the Center of Excellence is time restraints. Some clinical trials require a significant time commitment from participants and all of the studies require time from the medical staff. Another challenge is keeping study participants involved. Although caregivers and family members are usually able to maintain their involvement in studies, it is difficult for HD patients to continue committing to studies as their disease progresses.
PHAROS or the Prospective Huntington At Risk Observational Study monitors individuals who are at risk for HD but have not received genetic testing for the HD allele. By recording characteristics of these participants over time, researchers hope to better understand the progression of HD. At the HCMC Center of Excellence, Dr. Martha Nance is the Primary Investigator and Dr. Scott Bundlie is the independent rater who separately scores participants to ensure that the data is consistent. Ms. Radtke showed HOPES some of the PHAROS tests that are conducted at the HCMC Center of Excellence. Participants are monitored through performance on a verbal fluency test, the Stroop Test, the UHDRS, and questions about frequency and severity of behavioral symptoms.
The PREDICT-HD study is similar to PHAROS, but enrolled subjects are certain that they have the HD allele. The brains of both participants with HD and participants who are at-risk for HD are monitored and compared to better understand the neurological changes associated with HD.
2CARE is a phase III clinical trial investigating the therapeutic effectiveness of the anti-oxidant coenzyme Q10. Enrolled subjects have responded with enthusiasm to this drug trial. To learn more about HD and coenzyme-Q10 click here.
Support and Outreach
The HCMC Center of Excellence works with the Minnesota Chapter of HDSA to offer support for HD families and caregivers. You can visit the HDSA website for the Minnesota Chapter by clicking here. There are monthly support group meetings facilitated by social worker Jessica Hancock. The groups are held in three different regions for the convenience of HD families: the Twin Cities, Northern Minnesota and Northwest Minnesota. In addition to giving HD families an encouraging environment, the support groups will occasionally have guests from the HD clinic to give presentations about health and medical topics. An annual Minnesota HD conference in September gives these groups an opportunity to meet with each other and hear from others who are closely involved with HD, like healthcare workers.
There are also collaborative efforts within the HD community to hold events to raise money for HD. Among these events are an annual Hoop-a-thon started by a local high school basketball player whose mother has HD. The Hoop-a-thon increases HD awareness and raises funds for HD medical research. Events such as the “Hits for Huntington’s” Golf Classic and “Hunt for the Cure” Charity Paintball Big Game also raise money for HD organizations and research.
Several HD families have taken the initiative to reach out to the community and encourage people to learn more about HD. One family whose inspiring story has increased awareness about HD within their community is the Johnson family. The family cares for Mr. Johnson’s childhood friend, Cory Daniels, who was diagnosed with juvenile HD at the age of eighteen, Cory was only given eight months to live when he was put in the care of the Johnsons. HOPES had the opportunity to speak with Mr. Johnson’s wife, Heather, who worked as a registered nurse at a long-term care facility where Cory lived. Heather reconnected the childhood friends who lost touch after high school The Johnsons were aware that community care is more beneficial for patients than institutionalization, so they worked hard to obtain certification so Cory could come to their house to live. Cory has been with the Johnsons for over four years despite physicians’ predictions that he would only live for another eight months. Through organizations like the HCMC center of Excellence and the Minnesota Chapter of HDSA as well as individuals like Cory and the Johnsons, the HD community in Minnesota hopes to continue providing support to one another and increase awareness about HD.
HOPES would like to thank the HDSA Center of Excellence at HCMC and Dr. Nance for allowing us to experience first-hand a clinic that provides quality care to HD patients. We would also like to extend our thanks to Research Coordinator Dawn Radtke for helping to arrange the visit and the Twin Cities Metro Area HD support group members for allowing HOPES to join their July meeting. To visit the website for the HCMC Center of Excellence click here.
Drug Summary: Vitamin E is commonly found in the diet, in oils, margarine, and dressings. It is a lipid-soluble vitamin that protects cell membranes and other lipid-containing substances in the body, by interacting directly with free radicals and neutralizing them to prevent oxidative damage. Vitamin E could potentially help treat neurodegenerative diseases such as HD by protecting nerve cell membranes (which are made of lipids) from oxidation by free radicals, which can lead to cell death. (For more information on free radical damage, click here.) Studies in people with Parkinson’s disease or Alzheimer’s disease have shown some correlation between higher vitamin E intake and decreased risk of developing these diseases. (For more information on Alzheimer’s and Parkinson’s, click here.) However, there have been contradictory results in studies that tested whether vitamin E treatment could slow the progression or improve the symptoms of these diseases. Not many studies have been conducted to test the effects of vitamin E in people with HD. Unfortunately, the few results that exist have been inconclusive, with some indicating only slight benefits among some patients with mild symptoms, while others suggesting that vitamin E could potentially even have negative effects on health.
What is vitamin E’s role inside the body?
Vitamin E is lipid-soluble, meaning that it dissolves in fats. It has to be ingested with minimal amounts of dietary fat to be properly absorbed in the gastrointestinal (GI) tract. Vitamin E exists in eight different chemical forms, but the most common form in the human body is called alpha-tocopherol (α-tocopherol). Alpha-tocopherol’s main role inside the body is to act as an antioxidant. Alpha-tocopherol is lipid-soluble, so it mostly exerts its antioxidant effects on parts of the cell that are also lipid-soluble, such as the cell membrane, an important part of the cell that is made of lipids. Because cell membranes are made of lipid molecules, they are vulnerable to oxidation by free radicals, which can lead to cell death. Alpha-tocopherol plays a very big role in protecting cell membranes by donating its own electrons to free radicals in order to neutralize them.(For more information on free radical damage, click here.) Although alpha-tocopherol loses its antioxidant activity once it donates an electron, other antioxidants like vitamin C can restore alpha-tocopherol’s antioxidant properties. (For more information on vitamin C, click here.)
Besides protecting cell membranes, alpha-tocopherol has also been shown to protect low density lipoproteins (LDL) from oxidation by free radicals. LDL’s are particles made of both lipids and proteins that carry fats and cholesterol through our bloodstream. Research shows that oxidized LDL may increase a person’s risk of developing heart disease. Alpha-tocopherol may therefore exert positive effects in people with HD not only by protecting nerve cell membranes, but also by helping to prevent other complications such as heart disease. (For more information on heart disease and other complications of HD, click here.)
In addition to having these antioxidant effects, alpha-tocopherol affects several other cellular mechanisms and is known to act as a blood-thinner. Blood thinners can help reduce one’s risk of heart attack and stroke by preventing the formation of blood clots in blood vessels. It is important to remember that taking high doses of a blood-thinning compound like vitamin E along with other blood thinners is not advised, and anyone who wishes to take vitamin E as a blood thinner should first consult their doctors.
Could vitamin E supplementation become a potential treatment for HD?
Several laboratory studies have shown that vitamin E has great potential as an antioxidant. One such study showed that another form of vitamin E, alpha-tocotrienol, protected nerve cells from increased free radical damage and toxicity caused by the neurotransmitter glutamate (Khanna, et al. 2003). Because the nerve cells of people with HD are especially sensitive to glutamate, the prevention of glutamate-induced oxidative damage is very important. (For more information on glutamate toxicity, click here.) In this laboratory study, treatment of nerve cells with alpha-tocotrienol not only decreased cell death but also helped them grow at a normal rate even when treatment with glutamate was continued.
The same researchers found that alpha-tocotrienol not only protects nerve cells by reacting with free radicals directly, but can also prevent free radicals from forming. Alpha-tocotrienol can prevent excessive oxidative damage by inhibiting an enzyme called 12-lipoxygenase (12-LOX), an effect independent of its antioxidant properties. Increased levels of glutamate around the nerve cells cause activation of 12-LOX within the cells, which when activated leads to a cascade of events that lead to production of free radicals and an influx of calcium ions into the nerve cells. These events eventually lead to nerve cell death. Alpha-tocotrienol inhibits 12-LOX from setting off this cascade by binding to it close to its active site. The active site is the spot where an enzyme would normally bind to other molecules, or substrates, in order to set off a reaction in the cell. 12-LOX normally binds to a molecule called arachidonic acid to set off the above-mentioned cascade of events. By binding close to the active site, alpha-tocotrienol prevents 12-LOX from binding arachidonic acid and setting off the reactions that would eventually lead to nerve cell death.
Besides laboratory findings, there is also some clinical evidence that increased intake of vitamin E may help reduce the risk of developing Parkinson’s and Alzheimer’s disease, both of which also involve increased oxidative stress. However, studies that tested whether vitamin E supplementation could help reduce symptoms or slow the progression of these diseases have had varied results. One study of a total of 341 people with Alzheimer’s disease showed that treatment with alpha-tocopherol was associated with a delay in the progression of cognitive symptoms when compared to the placebo group. The group treated with alpha-tocopherol also demonstrated a slower decline in their abilities to perform everyday functions. Research on the protective properties of vitamin E in Parkinson’s disease has been inconclusive in both animals and humans; some studies have shown vitamin E to be protective and others have not.
Peyser, et al. (1995) conducted a 1-year clinical trial with 73 HD patients who were randomly assigned to receive either alpha-tocopherol treatment or a placebo. Since vitamin E interferes with the absorption of vitamin A in the intestines, these researchers decided that subjects in the treatment group should also take a vitamin A supplement in order to prevent the potential development of Vitamin A deficiency. Because vitamin C can restore vitamin E’s antioxidant abilities after it has neutralized a free radical, the treatment group also received daily vitamin C supplements.
These researchers reported that they unfortunately were not able to obtain placebo vitamin A and C pills for the control group, so both the vitamin E treatment group and the control group ended up taking vitamin A and C supplements, which are also antioxidants. Giving both groups these additional vitamins could not produce the same strong evidence as would the use of completely neutral placebo pills. The control group may have also showed some sort of improvement simply because they were given these two vitamins. Furthermore, the vitamin E treatment group may have benefited from the additional vitamins. However, the researchers were still able to establish some specific effects of adding vitamin E to the vitamin A and C combination.
These researchers realized that participants responded differently to the vitamin E supplementation depending on which stage of HD they were in when they started treatment. In order to analyze the results, they split both the treatment and placebo group in two based on the participants’ initial scores on a neurological test. Participants who entered the study with a score of 45 or less were considered to be in the early stages of HD, and participants who had initial scores of more than 45 were considered to be in the late stages. Based on this grouping, the researchers showed that on average, early-stage participants who were treated with vitamin E improved on the neurological examination by the end of the study. Meanwhile, late-stage participants did not show this improvement. This study is important because it shows that vitamin E may have potential to slow HD progression caused by free radical damage, but only if treatment is started before severe nerve cell damage takes place.
A newer study by Kasparova et al. (2006) done on rat models of HD showed that administration of a combination of vitamin E and coenzyme-Q10 (For more information on coenzyme-Q10, click here.) could have potential benefits for HD patients. The rats received coenzyme-Q10 and vitamin E for 10 days before they were injected with 3-NP, a chemical that would create lesions in the striatum, resulting in symptoms similar to HD. Results showed that the increase of creatine kinase, an indicator of brain energy metabolism dysfunction, as well as the decrease of coenzyme-Q10, were prevented in the brain tissue of these rats as compared those in the control group. However, coenzyme-Q10 and vitamin E were not effective in preventing the decline of electron transport chain function (For more information on electron transport chain function and abnormalities in energy metabolism, click here.).
Risks of Vitamin E supplements
In recent years, researchers at John Hopkins University have reported that patients who take high doses of vitamin E (more than 400IU) had higher risks of death, although it remains unclear why. Vitamin E supplements typically contain 400-800IU (1IU = 2/3 mg), which meets the criterion for high dosage. The data is still inconclusive as to whether lower doses of vitamin E are also associated with this risk. Furthermore, the studies were conducted on older adults, and many of them had heart diseases and other diseases. Nevertheless, HD patients taking high doses of vitamin E should consult with their doctors and might want to consider taking other types of antioxidants.
In conclusion, while vitamin E has beneficial antioxidant effects, it may be toxic at higher doses. Further research needs to be completed to determine whether vitamin E can be a safe and effective therapeutic treatment for Huntington’s disease. As of Spring 2012, not many studies have been conducted investigating the relationship between vitamin E and Huntington’s disease specifically.
For further reading
- For a good overview of what vitamin E does inside the body, how it is linked to other medical conditions and how it relates to diet and nutrition, visit Oregon State University’s Linus Pauling Institute website.
- Fariss, et al. “Vitamin E therapy in Parkinson’s disease.” Toxicology. 2003 Jul 15;189(1-2):129-46.
This is a fairly complicated article that explains the role of oxidative stress in Parkinson’s disease and then reviews all the research that has been done on vitamin E treatment in Parkinson’s.
- Khanna, et al. “Molecular basis of vitamin E action.” The Journal of Biological Chemistry. 2003 Oct. 31;278(44):43508-15.
This is a very technical article that describes the experiments that showed that alpha-tocotrienol helps prevent nerve cell death by inhibiting 12-LOX.
- Peyser, et al. “Trial of d-alpha-tocopherol in Huntington’s disease.” The American Journal of Psychiatry. 1995 Dec;152(12):1771-5.
This article is of medium difficulty and describes the 1995 clinical trial of alpha-tocopherol in 73 people with HD.
- Sano, et al. “A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease.” The New England Journal of Medicine. 1997 Apr 24;336(17):1216-22.
This is an article of medium difficulty that describes the clinical study of 341 people with Alzheimer’s disease that tested the effects of alpha-tocopherol treatment along with another drug.
– A. Milczarek, 05/03/05, updated A. Zhang, 4/18/12More
Have you ever wondered how new medicines are discovered? The process of going from an important discovery in a science laboratory to a successful drug available to the public is complex, costly, and time-consuming. This process is often referred to as Research and Development, or the R&D pipeline. It has many stages that interact and feedback into one another, takes many years, and costs millions of dollars.
In a way, R&D is like searching for two separate needles in two separate haystacks. The process begins with a thorough search and identification of all the different biological pathways that are involved in the disease process. The goal is to identify one or more pathways that contain possible biological targets for treating the disease. After finding one or more targets, the next step is to find potential drugs that block or change how the target causes or contributes to disease; this can be done by either designing a drug based on knowledge of the target’s molecular structure and function, or by screening large libraries of chemicals and molecular compounds to find one.
A potential drug treatment may emerge from these extensive searches. However, this “candidate” drug is not yet available for treating patients. First, it must journey through more research, tests, and clinical trials before it is finally approved by the Federal government’s Food and Drug Administration (FDA). Only then, many years later (and after spending a lot of money!), might a new medicine be available to help patients with debilitating diseases. For every attempt, the probability of success is less than 1%. But thousands of scientists around the world are working hard to beat those odds every day, discovering new biological pathways to target and new chemicals to try for all sorts of diseases.
Let’s take a closer look at the steps of the R&D pipeline. Below is a brief overview of each stage, and you can read other sections of this article to get a more comprehensive look at that stage of the process and how it applies to HD research.
Before scientists can even begin to think about finding treatments for a disease, they must have a good understanding of the biology and chemistry involved in the disease’s molecular pathways. Basic research tries to understand how certain biological and chemical imbalances cause disease. Scientists must investigate everything, from the genes and proteins involved, to clinical symptoms and disease progression.
Target Identification and Validation:
While gaining a thorough understanding of a disease through basic research, scientists also attempt to identify biological targets- usually genes or proteins – that trigger or contribute to a disease. A biological target is a good place to start looking for a treatment. There are numerous genes and proteins involved in most diseases- so how can scientists know if they have picked the right one to target? Researchers generally perform experiments on animal models to assess whether the biological target they have identified is crucial to the disease pathway.
The next step is to find one or more drugs that might make a useful treatment. One way to find candidates is to search through, or screen, thousands of chemical compounds to identify potential drugs. Alternatively, if enough is known about the shape and function of the biological target, scientists may be able to design new molecules or drugs that change the way the target behaves in living cells and patients. As opposed to screening, this approach is often called “rational drug design.” A potential drug must interact with the chosen biological target, and modify it in a way that will cure the disease or decrease its effects.
Drug Development/ Pre-Clinical Animal Studies:
When a potential drug is discovered from a screen or rational drug design, it has much promise as a therapeutic drug. However, little is known about the safety and effectiveness of this so-called lead compound in animals or humans. All lead compounds must be thoroughly tested in at least two animal models to determine safe doses, understand side effects, and discover more about long-term toxicity.
Investigational New Drug (IND) Application:
After animal model studies have been completed, pharmaceutical companies must submit an IND application to the Food and Drug Administration (FDA) to continue drug development. If approved, it gives the pharmaceutical company permission to begin clinical trials which involve testing the potential drug in human participants. The IND application must include data from animal studies, information about the drug’s production, and a detailed proposal for human clinical trials. Unless the FDA specifically objects, an IND application is automatically accepted after 30 days and clinical trials can begin.
Clinical Trials: Phase I
Phase I clinical trials are also called “First-In-Man” studies. These studies are mostly concerned with safety, determining the maximum tolerated dose (MTD) of the drug in healthy volunteers that do not have the disease of interest. They also look for how the drug should be delivered (for example, by pill, injection, or IV fluid), how it is absorbed into different organs, how it is excreted from the body, and if it has any side effects. Approximately, 70% of potential drugs make it through this initial stage of testing.
Clinical Trials: Phase II
Once a safe dose of the potential drug has been found in healthy human participants, phase II clinical trials test it in participants with the disease of interest. Like phase I trials, these trials look for evidence of toxicity, and side effects, but they also look for evidence that the drug helps patients with the disease feel better in some way. These trials help to further refine the optimal dosage, in order to maximize beneficial effects and minimize harmful side effects.
Clinical Trials: Phase III
Phase III clinical studies are the most expensive, time consuming, and complex trials to design and run. They use a very large participant group, all of whom have the relevant disease condition. These studies determine if the drug’s benefits outweigh the risks (like side-effects and long term toxicity) in a larger patient group, and also compares the new potential drug with older, more commonly used treatments if any are already on the market.
New Drug Application (NDA):
The FDA must review results at the end of each phase to approve the drug before it can move into the next phase of trials. Once phase I, II, and III trials have all been successfully completed, the pharmaceutical company submits a New Drug Application (NDA) to the FDA. The results of all of the trials are given, as well as the results of animal studies, manufacturing procedures, formulation details, and shelf life. In short, they include everything that would be used to label the drug. If the FDA approves a company’s NDA, they can begin to mass produce and market the drug in the US. Pharmaceutical companies submit similar applications to authorities in Europe, Australia and elsewhere to market successful treatments there.
Clinical Trials: Phase IV:
Phase IV trials are done after a drug has been approved, officially manufactured, and put on the market. They are done to determine the absolute optimal dosages in case it needs to be refined, to look at the very long term safety and efficacy of a drug, and to discover any rare side-effects. Phase IV trials are also used to identify the potential for new indication studies, meaning that the same drug may be able to treat diseases other than the one for which it was initially tested.
Basic research is concerned with understanding the background biology and chemistry underlying the mechanism of a disease. Scientists identify the genes, proteins, and specific types of cells involved in a disease and investigate how they contribute to the disease state. This type of science research is usually conducted in academic laboratories and research institutes around the world, and is less likely to take place in pharmaceutical companies. It is important to understand that basic science researchers focus their efforts on understanding the pathways and molecules involved in the disease- they don’t concentrate on finding a treatment. This information is then used by scientists in other research fields, such as drug discovery and therapeutics, to aid in the identification of drug targets and possible disease cures.
Usually, a research laboratory will concentrate on a few molecules or proteins in a disease pathway and try to discover as much as they can about those molecules. They may study the molecular structure of the molecule, how it usually functions in normal cells, and figure out what other proteins and genes it is related to or interacts with. Scientists will look at how their molecule (or molecules) of choice changes in diseased cells – if it works too much, stops working, or starts interacting with parts of the cell in a way that causes damage. All of this basic research helps to determine whether this molecule should be investigated as a biological target- the next step in the R&D pipeline. Although not all basic research directly contributes to a drug treatment, it all has the potential to, and so it is important to continue to strongly support basic science research programs to provide a solid foundation for drug development research.
Scientists often use model systems to study the genes and proteins involved in a disease. These can be in vitro, which is a useful way to isolate specific molecules and determine if they interact with one another in any way. Model systems can also be in vivo, which are more useful for studying specific molecules in the context of a disease, to see how they change a cell. In vivo model systems are also used to study the progression and development of a disease throughout an animal’s lifetime. The most common kinds of models include mice, yeast cells, worms, flies, rats, and human tissue culture.
HD and Basic Research
The HD community is doing a lot of basic research. We have much of this information located elsewhere on the HOPES site.
- For more information on the kinds of institutions and programs that do HD research, click here.
- For information on HD research going on here at Stanford University, click here.
- To find out about the techniques that scientists use in basic HD research, click here.
- To get an in-depth look at the day-to-day workings of a few research laboratories that conduct basic HD research click here.
Target Identification and Validation
Basic research on the genes, proteins, and molecular pathways involved in a disease, may assist in the discovery of a biological target. Since there are many genes and proteins involved in most disease pathways, there needs to be a way to identify which ones would be worth targeting for creating a drug therapy. A biological target is a molecule that may hold the key to a disease- it may greatly contribute to, or possibly be the direct cause of a disease.
Validation of the molecule as a biological target usually requires answering two questions. The first asks if the target is relevant to the disease, by examining if a change in the biological target results in a change in the disease. If a certain molecule is produced in a mutated form, in abnormally high quantities, or abnormally low quantities in a disease, it is usually a good biological target. Secondly, if a biological target is proven relevant to a disease, it is then important to determine whether it is drugable – that is, can it be targeted or changed by treatment with a drug.
It is important to remember that validation occurs throughout many stages of the R&D pipeline, including the basic science research, the drug discovery, and the development processes. What may appear effective in a tissue culture model may not work in a mouse model. In each stage of testing or clinical trials, if evidence indicates that a biological target is either not relevant or not drugable, then development of the treatment will stop. The scientists and pharmaceutical companies must then go back to the drawing board. This occurs fairly often, making drug discovery and development a difficult, costly, and time-consuming process. It does not mean that scientists made a mistake earlier on in the process, simply that a different experiment revealed that the target would not be suitable for drug development after all.
HD and Target Identification
A number of biological targets have been identified in the HD research field. First, there is the possibility that the altered HD protein itself may be a good target. It has been well-established as crucial to the disease, but it remains to be seen if it is drugable. Many animal models have shown that once neurodegeneration has begun, elimination of the altered HD protein halts the course of the disease (see Yamamoto 2000 in Cell, or click here for more information). At the same time, little is known about the normal function of the HD protein. We do know that huntingtin is critical for the creation and development of nerve cells, and that mice without the HD gene do not survive to birth (see Reiner 2003 in Molecular Neurobiology, or click here for the abstract.
In addition to the altered HD gene, many other genes, proteins, and molecular pathways have been identified as being involved in the HD disease pathway and its clinical symptoms. We know that molecules involved in energy production, apoptosis, and free radical damage (among others) contribute to HD. It is entirely possible that one of these pathways may have a good biological target that is drugable. For more information about many of the pathways and biological targets being currently examined and developed, click here.
Identifying and validating biological targets is a huge priority in the HD research community. Many basic research labs at universities and private institutions are devoted to this undertaking. The High Q foundation is a non-profit organization that works to bring together academia, industry, governmental agencies, and other funding organizations to identify and validate new therapeutic targets for HD. Recently, proteins like caspase-6 and Poly(ADP-ribose) polymerase (PARP1), have been identified as promising therapeutic targets.
Once a biological target has been identified and has passed preliminary validation, the next step is to identify candidate drugs that can modify the target’s actions in living tissues and cells. One way of finding potential drugs is to screen through the thousands of available drugs and compounds to see if any interact with the target in the desired manner. When screening, it is important to consider if the desired effect of the drug is to inhibit or enhance the normal activity of a biological target. A thorough understanding of the target’s biochemistry can sometimes enable scientists to guess what kinds of drugs and chemical compounds will interact with it. This can lead to a narrowed, more efficient screen.
In a full-scale screen, there may be more than 10,000 different molecules to look through. Pharmaceutical companies use combinatorial chemistry and high throughput machines to screen chemical compound libraries, looking for interactions between a potential drug and the biological target. They continuously narrow down the drug candidates, refining the search and the criteria they are using until a likely group of compounds is identified. Scientists also have to verify that any candidate drugs are very specific to the biological target- meaning that they interact with only the target, and not any other important molecules in a cell. If a compound interacts with too many molecules in addition to the specific target, it will often cause problems independently of its work in curing the disease. In this case, the side effects it causes would not make it a suitable drug treatment.
After a high throughput screen, a group of chemical compounds may be identified as potential drugs. These compounds will then undergo further testing; scientists will often use biochemistry to modify one of the compounds- this process is called optimization. These modifications can increase the drug’s effectiveness and make sure it doesn’t target other proteins. After this process, one or two molecules will be put forth for drug development. The most promising one is called the “lead compound”, and another is designated as a “backup”.
In the past many drugs were discovered by trial and error, or by chance through a screen. More and more often now, scientists are using a process called “rational drug design” to design and create a lead compound, instead of finding one in a screen. In rational drug design, scientists use knowledge about the three dimensional structure of the chosen biological target’s active site to design a drug to specifically interact with it. This requires a good knowledge of chemical biology to synthesize molecules and modify their shape so that they may serve as a drug. While many techniques for rational drug design are still being developed, it seems like it will be a good way for scientists to produce targeted and effective drugs with few unwanted interactions or side effects.
HD and Drug Optimization
The HD research community is helping to pioneer a new approach to drug development, using biotechnology in combination with traditional pharmaceutical approaches. In HD, every case has the same cause (the mutation in the HD gene), unlike diseases like Alzheimer’s disease, cancer, heart disease, and diabetes, which can be caused by a variety of different factors in individual patients. This allows HD researchers to use biotechnology to develop new treatments to target early disease time points, before the onset of symptoms, as well as treatments for particular symptoms. To learn more about the progression of HD and the onset of symptoms, click here Traditional pharmaceutical companies often develop treatments by modifying a relatively small number of existing drugs to target symptoms that are common in a number of different diseases. But the advent of new biotechnology approaches like those used by many HD researchers have recently started to force the pharmaceutical industry to look into finding other types of rational biological targets. Currently, pharmaceutical companies and biotechnology companies are forming partnerships to do just that.
There are many institutions and pharmaceutical companies devoted to HD drug discovery research. At Harvard Medical School, the Laboratory for Drug Discovery in Neurodegeneration (LDDN) is set up like a small biotechnology company. They have high-throughput screening robotics, a chemical compound library with nearly 100,000 different drugs, and staff and collaborators from all over Harvard University. Their goal is to find lead compounds and then hand them over to larger pharmaceutical companies for further testing and development. Since it doesn’t have investors to pay back like pharmaceutical companies often do, researchers have more freedom to pursue high-risk but high-payoff biological targets. Their projects focusing on HD involve screening their compound library for molecules that interact with and/or affect polyglutamine repeats polymerization, and kinases.
CHDI, Inc is a non-profit drug discovery and research organization based in Los Angeles, California. They are sponsored by the High Q Foundation a private philanthropic foundation that was established to bring together academia, industry, governmental agencies, and other funding organizations in the search for HD treatments. CHDI, Inc is a “dry” lab, meaning that rather than conduct experiments at their own facilities, they contract out projects to established laboratories that have the most relevant equipment, supplies, and scientists for the specific experiments. They collaborate with private and academic labs to do research on all aspects of drug discovery and development, from high throughput screening to preclinical development. One of their most recent projects is to partner with Amphora Discovery, a drug discovery and development company that has developed their own high throughput screening process, to find compounds that inhibit caspase-6 activity. For more on caspase-6, click here.
Medivation is a company dedicated to research and drug development in HD, Alzheimer’s disease and Prostate Cancer. They work with drugs from the pre-clinical stage through Phase II trials. One of their newest products is a drug called Dimebon, which is an antihistamine that is thought to alleviate symptoms and prevent progression of neurodegenerative diseases like Alzheimer’s and now is being tested for its effects in HD. For more information on Dimebon, please click here).
Drug Development/ Pre-Clinical Animal Studies
Once a lead compound is identified, it must be tested for toxicity in animals. Scientists are usually required to test the lead compound in two types of animals, typically a rodent and a larger animal. It is important to note animal models are not used in these tests for toxicity, meaning that they do not have the relevant disease condition. While animal models are often used in basic research and in target identification, healthy animals are used in these studies so scientists can determine the baseline levels of toxicity. Researchers test many dosage variables of the compound by administering various concentrations to the animals, changing how often the drug is given (frequency), and how long the drug is administered for. The drug can be administered in a chronic regimen, meaning it is administered frequently to keep the concentration at a constant rate. Alternatively, it can be administered in an acute regimen, meaning that it is given in an initial high dose and then is eliminated from the body.
Essentially, these studies are looking for the best treatment regimen with the least amount of toxic side effects. This is the therapeutic window, the dosage range in which the benefit of the drug outweighs its toxic effect. Throughout drug development and animal testing, researchers are also investigating the pharmacokinetics and pharmacodynamics of the lead compound.
Pharmacokinetics essentially looks at what the body does to the drug, and usually is characterized by the ADME, or absorption, distribution, metabolism, and excretion of the compound. Pharmacodynamics looks at what the drug does to the body. This looks at the dose-response relationship, and what effect the drug has on each of the major organs within the animal. It looks for any evidence that the drug is mutagenic (causes DNA mutations), carcinogenic (causes cancer), or teratogenic (causes problems with fetal development). Researchers also look for any long term or delayed effects in the animals.
HD and Pre-Clinical Development
There is a good deal of research in the HD community devoted to drug development, although more biological targets are needed for the field to grow much more. Among its many activities in drug discovery and development, CHDI, Inc has recently contracted with Edison Pharmaceuticals, Inc to develop new formulations of Coenzyme-Q10 that will act as more targeted forms. For more information on Coenzyme-Q10, click here.
VistaGen Therapeutics, Inc., a pharmaceutical company devoted to the discovery and development of small molecule therapies using stem cell technology has recently been awarded a grant from the NIH to do pre-clinical development of AV-101. This is a drug candidate with the potential to reduce the production of quinolinic acid, a neurotoxin produced in the brain that is believed to be involved in HD.
Clinical Trials: Phase I
A clinical trial is an important experimental technique for assessing the safety and effectiveness of a treatment. The most important purpose of a phase I clinical trial is to investigate the safety of a potential drug in humans, but it is also used to examine the pharmacokinetics and find the maximally tolerated dose.
For almost all phase I clinical studies, the participants should be healthy males and females from ages 18-40 who are not taking any additional medication. Usually, 20-100 participants are used in these studies. These trials are uncontrolled, meaning that all participants are given the drug. Each participant serves as their own control, because their health before and after the drug treatment is assessed and compared.
When beginning a phase I trial, researchers have to start with a certain dosage, look at its effects, and then slowly scale it up until they reach what they feel is the dose-limiting toxicity. This is the dosage at which side-effects are severe enough to prevent the participants from benefiting from the treatment. The dose previous to this one is considered the maximally tolerated dose, and is used in phase II clinical trials.
Furthermore, the toxicity of the drug and its effects on each of the major organs is carefully studied at each dose level. The pharmacokinetics of the drug- how much a change in dose affects the distribution, absorption, and elimination of the drug from the body- is examined as well. Participants are usually observed until several half-lives of the drug have passed. Essentially, by the end of a phase I clinical trial, researchers should have a recommended dose to use in phase II trials, a good idea of the pharmacokinetics of the drug, and notes as to any benefits they may have seen in the participants. Approximately 70% of drugs tested in phase I trials make it to phase II. Potential drugs that fail in phase 1 trials, usually do so because too many harmful side effects are produced that outweigh the benefits to justify using it as a kind of treatment.
HD and Phase I Clinical Trials
There are currently many clinical trials being conducted to study potential treatments for HD. Because the HD community is relatively small, it is possible to have good communication and coordination between researchers all over the world. The Huntington Study Group has been organizing and conducting clinical trials for HD since 1993. The HSG is a non-profit organization that is composed of physicians and health-care providers from around the world. They support open communication across the scientific community and full disclosure of all clinical trial results to the public.
Encouragingly, many clinical trials for potential HD therapies in progress at the time of writing have moved from phase I into phase II and III. As of March 2007 the University of Iowa is conducting a Phase I trial on a selective serotonin reuptake inhibitor (SSRI) called citalopram. For more information on this trial, please click here The National Center for Complementary and Alternative Medicine (NCCAM) has completed a phase I trial with an amino acid derivative called creatine for patients with HD. However, because it is thought that creatine will be more effective when used in combination with other drugs, additional research will first determine what other drugs it should be paired with before it is tested in phase III trials.
For information about clinical trials in every phase, the NIH runs a database that compiles all known trials in the country. For their list of trials related to HD, click here. Finally, there are ways for HD patients and their families to get involved with clinical trials for potential HD treatments. Huntington’s Disease Drug Works is a program designed to facilitate communication between HD patients and their families, and the scientists and doctors conducting the latest research on Huntington’s disease. Their hope is to speed up research and reduce the time it takes to set up a clinical trial. Through their website, you can find ways to enroll in a trial as a participant, or volunteer to help out those who do participate.
Clinical Trials: Phase II
The main purpose of phase II is to gather preliminary evidence as to whether the potential drug helps participants with the relevant disease. Phase II trials are also used to determine the common short-term side effects and risks associated with the drug in patients with the relevant disease. The participants in these studies, anywhere from 100-300 affected individuals, are usually closely monitored. Rare side effects will probably not be seen because the phase II participant population is too small.
Phase II trials are sometimes randomized, which means that half the participants in the study are chosen at random to receive the old or “standard” treatment, and half are chosen to receive the new treatment. Furthermore, these trials are often double-blinded, which means that neither the participants nor the clinical researchers know who has gotten which treatment. This eliminates bias on the part of the researchers, both in terms of deciding who would get the new treatment, and in observing or measuring the results.
A successful phase II trial is necessary to convince the scientists and physicians conducting the clinical trials that it is worthwhile to move into a phase III trial, which is very costly and time-consuming. Scientists must look at various measurable factors (outcomes) to decide whether the phase II trial was successful. If the drug being tested seemed to reduce or improve symptoms, nerve cell loss, tumor size, blood pressure, or any other relevant outcome in comparison with the control group, they will consider proceeding with a phase III trial.
A phase II trial can take up to two years, and even if successful, does not guarantee that a phase III trial will also be successful. It is important to note that only about 30% of all potential drugs make it through phase I and phase II trials. Even if the drug does make it this far, many problems may become evident once it is used in a larger participant population. This uncertainty is simply one of the many risks that all drug developers and clinical researchers take during research and development.
HD and Phase II Clinical Trials
A few different HD treatments are being studied in phase II trials as of April 2007. The Huntington’s Study Group is sponsoring a trial to look at the long-term safety and efficacy of minocycline in reducing symptoms for patients with HD. This phase II study is being conducted at multiple centers across the US, and is enrolling about 100 participants. For more information on this study, please click here.
Another phase II trial is being conducted at the University of Iowa to examine the effects of atomoxetine on daily activities such as attention and focus, thinking ability and muscle movements in subjects with early HD. This treatment is mostly aimed at relieving the cognitive symptoms of HD, and the drug has been successful in treating similar symptoms in patients with ADHD. The trial is currently recruiting participants; for more information, please click here.
It is important to remember that only a small percentage of all clinical trials are successful. In 2001, a phase II trial was conducted to test the effectiveness of the drug amantadine for the treatment of chorea associated with HD. Amantadine blocks the action of glutamate, which is thought to be implicated in HD toxicity. For more information on the role of glutamate in HD, please click here. The drug has had some success in relieving symptoms in patients with Parkinson’s disease. However, the phase II clinical trial indicated that, in fact, amantadine had little effect on Huntington’s chorea, and so it was not continued into a phase III trial. For more information on this trial, click here.
Clinical Trials: Phase III
Phase III trials serve as the definitive experiment to determine if a potential drug is effective and should be available for routine use in patients. If there is no treatment available for the disease in question, a phase III trials tests the effectiveness of a new drug against a placebo or no treatment. When there are established treatments, the point of a phase III trial is not to test the effectiveness of a potential treatment, but to test if it is more effective than the established treatment. This is always done by comparing two treatments- usually, the new treatment with a standard one. Sometimes trials use the same type of drug for both categories, but compare a new dosage regiment with an old one. Like phase II trials, all participants have the relevant disease. Phase III trials typically enroll large participant groups, anywhere from 1000-7000 people. It is important to have a large group so that researchers can identify any benefits or side-effects, no matter how small they are. Like phase II trial, phase III trials are randomized.
Designing and conducting a phase III clinical trial is very difficult. It is very time-consuming and costly, and it must be done carefully to ensure valid results. Data analysis is very complex, especially when researchers are not simply looking for changes and effects that are very concrete and easily measurable, like the number of people who survived. Researchers often look for changes that can be measured on a scale, like the improvement of symptoms. These can be difficult to judge and compare between patients being treated with the potential new drug and those patients treated with an existing drug. However they are important to analyze and understand so that the benefits of the new potential treatment can be determined. It is also important that researchers recognize any significant differences in response between genders or ethnic groups.
HD and Phase III Clinical Trials
As of April 2007, several phase III clinical trials are in progress, testing new treatments for HD. Enrollment was completed in August 2006 for a trial sponsored by the Huntington Study Group testing the effects of ethyl-eicosapentaenoate (ethyl-EPA) on HD chorea. Ethyl-EPA is thought to keep nerve cells healthy, inhibit apoptosis, and reduce free radical damage. The trial itself is underway, and is composed of at least two 6-month phases, and is slated for completion in September 2007. For more information on this study, please click here
A phase III trial has just finished recruiting participants for a three year study on the long term effects of the drug riluzole. Riluzole has been used to slow the progress of amyotrophic lateral sclerosis, a related neurodegenerative disorder. This study is sponsored by Sanofi-Aventis, and is testing whether riluzole has long term effects on HD chorea and on total functional capacity (TFC) of affected patients. For more information on riluzole, click hereand for more information on this clinical trial, please click here
Prestwick Pharmaceuticals has recently completed a phase III trial using tetrabenazine to treat HD chorea. Tetrabenazine is thought to reduce the amount of dopamine in nerve cells, and this may reduce the severity of chorea. Tetrabenazine is also used to treat chorea in other neurodegenerative disorders. Initial results have shown that it is better than a placebo. Prestwick filed an application with the FDA to market tetrabenezine, and in April 2006 received a letter from the FDA stipulating the conditions which they must meet to make it an available treatment. The FDA also designated tetrabenazine a fast track product because there are no other drugs available in the U.S. to treat chorea. However, Prestwick’s formulation is already marketed in at least 8 countries outside of the US, including Canada.
Clinical Trials: Phase IV
Phase IV trials are conducted once a new drug has been approved for marketing and is available for prescription by doctors. Occasionally, government authorities (usually the FDA) may require a pharmaceutical company to do a phase IV study, while sometimes these studies are voluntarily conducted. A company might want to know more about the side effects and safety of the drug, or how the drug works in the long term. They also look at how the drug impacts the average participant’s quality of life. Many phase IV trials are also used to determine the cost-effectiveness of the treatment, and compare it to any alternatives available.
Many drugs have very rare side effects that only appear in 1 of every 10,000 participants, or less frequently. Because phase III clinical trials have only a few thousand subjects and only last for a couple of years, these side effects may not show up in the earlier trials. Phase IV trials are particularly useful in helping to discover and monitor these rare side effects. They are also used to look at the effects of the drug in specific sub-categories of the participant population, such as children and the elderly. If many unexpected and severe side effects are detected in the phase IV trials, the drug can be withdrawn or restricted, despite its earlier approval from the FDA.
Additionally, phase IV trials might discover that the drug can be used to treat conditions other than the ones it was originally intended for. If the drug seems promising as a new treatment for a different condition, a pharmaceutical company can take the drug back to phase III clinical trials (called a new indication study) to get approval for multiple uses.
For Further Reading
- About Clinical Trials Online
A useful site from the Huntington’s Study Group that discusses the various phases of clinical trials in more detail.
- Background Information for Clinical Research in Huntington’s Disease. Online
A resource from HD Drug Works discussing the types of clinical trials that are conducted for HD
- Clinical Trials currently being conducted for HD. Click here.
A service of the U.S. National Institutes of Health
-J. Seidenfeld, 5/19/07More
In April 2007, HOPES researcher Justine Seidenfeld visited the Baltimore Huntington’s Disease Center (BHDC) in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, MD. The BHDC has been designated as a Center of Excellence by the Huntington’s Disease Society of America (HDSA). Centers of Excellence are recognized not only for the quality and scope of care they provide for their patients, but also for their clinical and basic research efforts, and the outreach services they provide to the general community. For more on the HDSA’s Center of Excellence program, please click here. The Baltimore Huntington’s Disease Center serves most of the mid-Atlantic region, providing services to Maryland, Pennsylvania, Delaware, New Jersey, Washington DC, and Virginia.
HOPES would like to thank the Baltimore Huntington’s Disease Center, particularly Mr. Abhijit Agarwal, Ms. Kit McFarland, Ms. Debbie Pollard, and the director of the Center, Dr. Chris Ross, for taking time out of their busy schedules to speak with us and share their perspectives on Huntington’s disease research.
The Baltimore Huntington’s Disease Center is the only HDSA Center of Excellence based in a psychiatry department (instead of a neurology department) of a medical school or hospital. As such, the Center can pay special and expert attention to treating the psychiatric and psychosocial aspects of the disease, for which we now often have effective symptomatic treatment. However research focuses mostly on brain imaging, neurobiology, genetic mouse models and other basic science, and clinical trials of new therapeutic agents. For more information on the symptoms of HD, click here.
Ms. Debbie Pollard is the clinic coordinator at the BHDC, and she helps patients when they first come to the Center. Ms. Pollard performs full physical exams for each patient to initially determine what symptoms they have, takes a full family and personal health history, and helps to generally guide patients as to how the center works and what services they provide.
The Center runs two separate multidisciplinary clinical programs to provide services to incoming HD patients. Additionally, there are related social services (such as community resource referrals and housing assistance) available in both programs. Confidentiality is strictly upheld in all cases and practices.
One of the clinical programs is an “Evaluation and Research” program, which runs every Tuesday from 1-4pm. The program is over 25 years old, and is supported by the HDSA and the National Institutes of Health (NIH). Thanks to these research grants, all of the services are (presently) provided with no charge. Patients can either make an appointment to come in on their own, or they may be referred to the Center by other physicians or neurologists in the area. At the first meeting, a number of neurological and psychiatric evaluative tests are conducted in addition to the detailed medical and family history that Ms. Pollard takes. Individuals who do not know if they have the altered huntingtin gene, but are presenting some of the symptoms of HD, can take a genetic test for HD (or other potential neurodegenerative disorders) if they so wish. Other staff members of the BHDC may see the patients for follow up services like consultations, case management (including symptomatic treatments for chorea or anti-psychotics if appropriate), counseling, and referrals if it is necessary.
The second clinical program offered at the Baltimore Huntington’s Disease Center is the “Continuing Care Program”. This program offers ongoing medical care for HD patients, as well as counseling and social services for them and their families. The primary purpose of the clinic is to treat and manage HD symptoms through medication, counseling, and to help patients to adjust their environmental surroundings. Patients can be referred to see staff members at the center who serve as neuro-psychiatrist specialists, social workers, or be referred for occupational therapy and speech therapy. The goal of the staff is to work with patients and their families to develop a tailored program for care. As opposed to the “Research and Evaluation” program, services from this program must be paid for, but health insurance is accepted when it applies. However, a generous grant from the HDSA allows the BHDC to charge for services based on the patient’s ability to pay and provide services for free to individuals that cannot otherwise afford it.
The clinic also conducts genetic tests for family members of those with HD who want to know their gene status. Genetic testing is a serious issue, and should only be undertaken after much consideration and counseling- for more information about genetic testing for Huntington’s Disease, please click here. They also offer counseling to many asymptomatic individuals who have the altered HD gene, in order to help them adjust to the kinds of lifestyle changes they can anticipate when symptoms begin to appear. Ms. Pollard emphasizes that as a Center of Excellence, the clinic is open to anyone regardless of the ability to pay, so anyone may come in for these services.
Social worker Ms. Kit McFarland explains that the BHDC is mostly a research operation that also provides care to patients. A large part of Ms. McFarland’s job is to provide tailored information about HD to families or individuals who have specific concerns. She also puts together an initial package of basic information for those who are unfamiliar with HD to use before they need more specialized help. Much of the time, the people who come to her for advice are families who have just learned that HD runs in their family (usually after one member was diagnosed with it) and they desire more information.
Ms. McFarland feels her job as a clinical social worker is to generally help people learn how to best support and stay involved with their family members that have been diagnosed with HD. For example, she gives them tips to help them make certain that the member of the family with HD stays well-nourished, such as using Ensure shakes. For family members who act as caregivers, she often finds that it is difficult for them to understand how their loved one will change behaviorally throughout the course of the disease, and so she tries to provide ways for them to cope with this issue. They may commonly encounter violent reactions from the family member with HD, but sometimes it can be hard to tell if it is intended violence or a motion from chorea. For those afflicted with HD, one of the most difficult parts of the disease is the gradual loss of their freedom- particularly when in comes to driving. If it comes time for the HD patient to stop driving but they refuse, Ms. McFarland might tell the family members or caregiver that the patient needs to be taken for a driving test, and tries to get the family involved in this decision. For more on HD and driving, please click here.
Another one of Ms. McFarland’s chief tasks is to provide help to the outside community, particularly those who have reached the stage of HD where they need some kind of assisted living arrangement- either in nursing homes or other facilities. This is a difficult process because many individuals with HD are often not prepared to relinquish their independence, even when it is necessary. She also works directly with employees of nursing homes and assisted living facilities in the area to teach them skills they need to serve residents with HD. She explains that many of the issues that nursing home or assisted living facility employees will encounter with their HD residents are actually very common among individuals of that age- such as problems with getting residents to eat. The major differences in residents with HD, that pose greater problems to the staff, are very rapid weight loss and aggression. For more on the manifestations of aggression in HD, click here. Ms. McFarland is also highly involved in much of the Center’s efforts to provide help, information, and services to those patients who have difficulties with transportation and cannot come to the center themselves.
Mr. Abhi Agarwal is the clinical research coordinator for the BHDC, and his job is to organize the enrollment and participation of patients in various clinical trials run through the Center. As Mr. Agarwal explains, the Center offers a wide range of opportunities for individuals and their families to participate in a variety of clinical research studies. Participation in these research trials is free of charge, thanks to a number of research grants from the National Institutes of Health (NIH), the Huntington’s Disease Society of America (HDSA), and the Huntington’s Disease Foundation (HDF).
Mr. Agarwal explains that they take a diverse array of approaches to looking at HD, conducting clinical studies that involve genetics, neuropathy, autopsy-based studies, fMRI studies, and basic research studies. He elaborates further on the clinical research studies currently being conducted at the Center:
1) The Longitudinal Core Study: This project is an observational study, which means that it is not intended to test potential treatments for HD, but rather is a study that will help advance our understanding of the natural onset and progression of HD. To enroll in the trial, the only requirement is to have undergone testing for the altered HD gene- participants don’t need to actually have HD, because control subjects are needed as well. Any patient that participates in the study at the BHDC is seen annually from their enrollment until their death, and at each yearly meeting they receive full neurological and psychological evaluations to assess the how far along motor, cognitive, and behavioral symptoms have progressed. They also receive functional magnetic resonance imaging, or fMRI scans on every other visit to look for structural differences in the brain over time (changes in the shape of the brain, usually related to nerve cell death), and to compare this to people who do not have HD. Because longitudinal studies often require large numbers of patients, the other goal for this study is to assemble a large database of patients who may be able to simultaneously participate in other clinical trials for HD. The Center has about 90 – 110 participants a year for this study.
Mr. Agrawal emphasizes that for observational longitudinal studies to get results, it takes time to be able to see statistically significant patterns that will further the understanding of HD. But these studies can provide critical information on the disease. For instance, the center has been able to demonstrate using sophisticated brain imaging, that striatal atrophy begins at least 10 years prior to clinical onset, that neuronal cell death correlates best with functional disability, and that the number of trinucleotide repeats in the huntingtin protein has an effect on the rate of HD progression. They found that individuals with the smallest number of trinucleotide repeats appear to have the best prognosis. For more about trinucleotide repeat lengths and the huntingtin protein, click here.
2) Genetic study for Huntington’s Disease-like 2 : Researchers at the Baltimore Huntington’s Disease Center are also very interested in looking for other genes that cause HD-like diseases. They have actually identified a number of these disorders, which are defined by having very similar symptoms to HD, but do not involve the altered HD gene- the HD gene can be perfectly normal and these symptoms may still appear. One of these diseases is called Huntington’s Disease-like 2 (HDL-2) and like HD, it is an adult onset neurodegeneration disorder, it is autosomal dominant, and it is characterized by chorea, cognitive, and psychiatric symptoms. It also involves neurodegeneration and inclusion bodies in the same parts of the brain as in HD. The Center is now working on a project to identify genetic markers for this disease, and to understand what kinds of mutations (other than the altered huntingtin mutation) could cause a disease like HD. They have recently published a paper in 2007, linking HDL2 to a glutamine/CTG repeat mutation on chromosome 16. This kind of mutation is related to, but not the same as the mutation involved in HD. They hope that by understanding the pathology behind HDL-2, it will shed new light on the pathology of HD and other neurodegenerative diseases.
3) Huntington Study Group trials : The BHDC participates in a number of multi-site clinical trials run by the Huntington Study Group. The Huntington Study Group is a non-profit organization composed of physicians, medical researchers and health-care providers from around the world. They have been organizing and conducting clinical trials for HD since 1993. In particular, the Center recruits participants for the observational PHAROS and COHORT studies, the PREDICT-HD study to find neurobiological markers of HD, and the completed TREND-HD study which is a therapeutic trial for Ethyl-EPA. For more on the Huntington Study Group, please click here, and for information on clinical trials in HD, please click here.
4) Memantine Study : The Center is also conducting a clinical trial with memantine, a drug that has already been approved by the FDA and marketed as Namenda for use in Alzheimer’s disease patients. However, not much is known about its use in HD, so the purpose of this clinical trial is to test if it will improve or delay cognitive symptoms of HD. The trial is sponsored by a company named Forest Pharmaceuticals, a company that produces drugs for cardiovascular diseases and CNS diseases like HD. This type of trial is a new indication study, and so it is run as a double-blinded, placebo trial over the course of 6 months. The Baltimore Huntington’s Disease Center started recruiting patients for this study in the fall of 2006, and as of March 2007 they have 72 participants. For more information on the use of memantine in HD, click here.
While anywhere from 150-200 people come in for clinical services in an average year, 2006 was an especially busy year for the clinic. Mr. Agrawal also explains that while many people come to the BHDC for genetic testing or patient care, about 25% to 50% of those who come also agree to participate in the clinical trials run through the Center. A good reason for any individual with HD to participate in the Longitudinal Core Study run at the Center is that there will be records of them kept in the Center’s database system, and so they can potentially be contacted to be recruited for any new therapeutic clinical trials if they fit the criteria needed to be included in the study.
Dr. Chris Ross is the director of the Baltimore Huntington’s Disease Center, and runs a research laboratory that focuses on the neuronal biology and genetics of neurodegenerative and psychiatric disorders such as HD, Parkinson’s disease, schizophrenia.
Dr. Ross discusses a few of the research projects conducted in his laboratory. He explains that the primary purpose of basic research is to identify biological targets for HD, and to develop those targets into treatments. For more on the process of going from basic research to a treatment, click here. As such, his lab focuses their research projects around potential biological targets for HD, and mostly on the huntingtin protein itself.
1) One area of current studies focus on how huntingtin aggregates are formed, and at what point these aggregates are toxic and cause nerve cell death. They have hypothesized that the larger aggregates or neuronal inclusions are not the most toxic molecules, but rather that the intermediates proteins in this aggregation pathway (the early aggregates) may be the most lethal form. As such, they may be the best molecules to target for future therapies. For more information on huntingtin aggregation, please click here.
Dr. Michelle Poirier, another faculty member at Psychiatry at the Johns Hopkins University School of Medicine, is doing studies in her own laboratory to investigate the shape or molecular structure of these intermediate huntingtin proteins. One of the most recent theories of how huntingtin protein aggregates are shaped describes them as made up of a series of folded strands of amino acids, with each strand composed of seven or eight glutamine amino acids. In a paper published in 2005, Dr. Poirier collaborated with the Ross lab to create two tissue culture models based on this theory. They confirmed that the proposed structure does indeed occur, and that there is a correlation between the presence of this type of huntingtin aggregate in the tissue culture cell and the presence of cell toxicity. However, they suggest that it is entirely possible that the toxicity is not caused directly by these aggregates, but rather that any of the kinds of intermediate species formed throughout the aggregate pathway may be responsible for toxicity instead.
2) Another project in the Ross lab looks at what kinds of proteins are involved in cutting the huntingtin protein into fragments. This process is also implicated in nerve cell toxicity in HD – it is thought that a fragment of huntingtin is actually more toxic to the cell than a full-length huntingtin protein. For more information on huntingtin protein fragments, please see figure P-2 here. In collaboration with Dr. David Borchelt and his laboratory at the University of Florida’s College of Medicine, Dr. Ross’ lab developed one of the initial transgenic mouse models of HD. Dr. Ross’s lab has used this mouse model to look at which enzymes play the largest role in generating toxic fragments of huntingtin protein. In collaboration with Dr. Michael Hayden’s laboratory they have already determined that caspase-6 is one of the most commonly involved enzymes in huntingtin fragmentation (please click here for a HOPES article on that finding), but they are looking at the role of other caspases and calpains (another family of proteases) as well.
Tamara Ratovitski, a member of the Ross lab, leads a related project using tissue culture models to look for the specific points in the chain of amino acids in the HD protein where fragmentation occurs. She wants to understand exactly how many fragments are generated by each type of protease, and how long they are. The goal is to target the most important proteases for inhibition, which will reduce the number of fragments and (presumably) cell toxicity.
3) A third project at the Ross lab looks at the affects of the mutant HD protein upon gene transcription. It is thought that the altered huntingtin protein changes the patterns of how genes are transcribed and translated, especially the genes that are key for a cell’s survival- and this may contribute greatly to toxicity in HD. Several years ago, Dr. Ross’ lab identified an unusual interaction between the mutant HD protein and the CREB-binding protein (also known as CBP), a smaller regulatory protein that is key for cell survival. For more information on the role of CBP in HD, click here.
Currently, the lab is following up this project with another group of studies intending to demonstrate a direct connection between the altered huntingtin protein, altered gene transcription, and cellular toxicity. It may be that the interaction between CBP and the altered huntingtin protein is one of a group of similar interactions between proteins involved in gene transcription and the altered huntingtin protein. If their research conclusively demonstrates that altered gene transcription does lead to cellular toxicity, one possible therapeutic intervention would be to use HDAC inhibitors. For more information on the potential role for HDAC inhibitors, please click here.
When asked what he thinks about the role of basic scientific research in respect to the larger body of HD research, Dr. Ross illustrates his opinion by discussing what goes on at the Baltimore Huntington’s Disease Center. Dr.Wenzhuan Duan, an assistant professor in the Department of Psychiatry and Behavioral Sciences works on research in Huntington’s and Parkinson’s disease. He takes biological targets identified through basic research on HD, and develops potential therapeutic drugs based on these findings. For more information on the process of drug research and development in HD, click here. They have developed a tissue culture model using nerve cells with the altered huntingtin protein that can be used to test potential therapeutic compounds to see if they might be useful for treating HD.
Dr. Ross emphasizes that another one of the major goals in doing therapeutic research is not only to cure HD, but to delay its onset. The idea would be to intervene by using treatments before the cognitive, motor, or behavioral symptoms actually appear. Members of the BHDC have already demonstrated that a great deal of neurodegeneration occurs before symptoms actually appear, so it would be effective if treatment occurred before the identifiable “onset” of symptoms to prevent or delay them. The Center has submitted a grant to conduct a phase II clinical trial to look at the effects of coenzyme-Q10 on presymptomatic HD patients, to see if it does in fact, delay the onset of symptoms. For more information of co-enzyme Q-10, please click here. The focus on research and treatments for presymptomatic HD patients is a very new direction for the Center, and appears to be a promising one.
For further reading
- The Baltimore Huntington’s Disease Center.
The website for this HDSA Center of Excellence.
- Rosenblatt A, et al. The association of CAG repeat length with clinical progression in Huntington disease. Neurology. 2006;66(7):1016-20.
This study demonstrates that individuals with the smallest number of trinucleotide repeats appear to have the best prognosis
- Reading S, et al. Functional Brain Changes in Presymptomatic Huntington’s Disease. Ann Neurology 2004;55;879-883
The 2004 publication demonstrating that there are significant structural changes in the brain in presymptomatic HD patients.
- Rudnicki DD, et al. Huntington’s Disease Like-2 Is Associated with CUG Repeat-Containing RNA Foci. Ann Neurology 2007;61;272-282
A follow-up study on HDL-2 demonstrating that it affects RNA function, and this may contribute to cell toxicity in HDL-2.
- Schilling G, et al. Characterization of Huntingtin Pathologic Fragments in Human Huntington Disease, Transgenic Mice, and Cell Models. J Neuropathology 2007. Vol 66, No. 4; 313-320
This publication demonstrates the location of significant sites of huntingtin fragmentation.
- Poirier MA, et al. A Structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Human Molecular Genetics, 2005. Vol. 14, No.6: 765-774.
This paper discusses the models for huntingtin protein aggregate structure, and further confirming the beta-strand/beta-turn model of aggregation.
- Wang W, et al. Compounds blocking mutant huntingtin toxicity identified using a Huntington’s disease neuronal cell model. Neurobiology of Disease. 2005;500-508.
This paper discusses a tissue culture model that has been demonstrated to be a good method to screen potential therapeutic compounds for treating HD.