A drug that lowers levels of the neurotransmitter dopamine to treat chorea, or the uncontrollable twisting motions that affect many people affected by HD.More
Chorea is one of the most common and debilitating motor symptoms experienced by people with Huntington’s Disease. Tetrabenazine (TBZ) has been the drug of choice for treating chorea in 10 countries for more than a decade. However, TBZ has not been widely used in the U.S. because, until recently, the drug had not been approved by the FDA for the treatment of chorea. In August of 2008, the FDA approved a form of TBZ, called Xenazine, for the treatment of chorea, making the drug available to HD patients in the U.S. TBZ is also available under the name Xenazine in Europe and Australia, and under the name Nitoman in Canada. According to reports from countries where TBZ has been used for a longer period of time, 80% of patients show an improvement in chorea. It is important to note that TBZ treats some of the symptoms of HD but is not a cure because it does not affect the underlying mechanisms or progression of the disease.
How does TBZ work?^
TBZ cannot fix the proteins that are damaged in HD, but it can help reduce one of their harmful effects: chorea. Recall that chorea is believed to be caused by increased activity of the neurotransmitter dopamine. TBZ exerts its anti-choreic effects by reducing the amount of dopamine in the brain in two ways. The first way and more widely recognized way is by preventing dopamine from being released into pockets at the end of each neuron called vesicles. These pockets store neurotransmitters, like dopamine, and release them into the synapse at certain times. When a signal to release the neurotransmitters is received, the vesicles are transported to the ends of nerve cells for release through the membraneof the neuron into the synapse. Special proteins called vesicular monoamine transporters (VMATs) are responsible for putting neurotransmitters into the vesicles. TBZ binds to the VMATs, preventing them from performing this function. As such, neurotransmitters like dopamine are not stored in vesicles and cannot be released into the synapse where they would otherwise affect other nerve cells.
The second way that TBZ reduces dopamine is by blocking dopamine receptors. TBZ binds to receptors on the surface of the receiving nerve cell, blocking dopamine from binding and passing on its message. The mechanism of inhibiting dopamine receptors, however, is thought to be less significant at the TBZ dosages used in HD patients. For more information on the neurobiology of HD, click here. Because it has the potential to block dopamine on both sides of the synapse, TBZ is thought to be that much more effective at treating choreic movement disorders.
What are the possible side effects of TBZ?^
TBZ depletes neurotransmitters other than dopamine in the brain, such as serotonin and norepinephrine. As a result, it can produce several side effects. By decreasing the amount of serotonin in the brain, TBZ may increase the risk of clinical depression. Also, as a dopamine-depleting drug, TBZ can sometimes lead to Parkinsonian motor symptoms. Parkinson’s disease is the result of too little dopamine in the brain, and is characterized by rigidity and difficulty initiating movement. It is very unlikely, though, that people with HD would get Parkinsonian side effects from using TBZ, as their dopamine levels are so high. For more information on the relationship between HD and Parkinson’s disease, click here. Among people with HD who experience side effects with TBZ, most report mild symptoms such as drowsiness, constipation, insomnia (already a common occurrence in HD), akathisia, drooling, and weakness.
What research has been done on TBZ?^
TBZ has been in use in countries outside the U.S. since 1960, so many studies have been conducted on the drug.
Mikkelsen (1983) studied the tolerance of TBZ during long-term use. The results of this study showed infrequent and usually mild side effects. Only 5 of 124 participants discontinued the use of TBZ because of adverse effects. The researcher concluded that long-term treatment with TBZ appears to be quite safe.
Pearson & Reynolds (1988) linked TBZ with dopamine depletion by examining brain tissue from people with HD. They looked at people who had been treated with TBZ during their lifetimes, and compared their levels of neurotransmitters to the levels of people who had never been treated with TBZ. They found that those who had received TBZ treatment had lower concentrations of neurotransmitters in all areas of the brain that they studied, compared to those who never received TBZ treatment. These researchers found the greatest decrease of neurotransmitter was dopamine in a part of the striatum called the caudate, an area of the brain important in movement. For more information on HD and the brain, click here. However, the decrease in neurotransmitter was not limited to dopamine, but also included serotonin and similar molecules, which suggested the possibility of side effects. This study confirmed the findings of animal studies that TBZ treats chorea by depleting neurotransmitters in the brain.
Ondo, et al. (2002) tested the efficacy and tolerability of TBZ for treating chorea in 19 people with HD. Participants started with dosages of 25 milligrams per day, with a weekly increase to 150 milligrams per day. These participants had the option of not increasing the dose if they were satisfied with the results at any given stage, or if they began experiencing negative side effects at higher doses. They were evaluated at the beginning and end of the study. These evaluations included a videotaped portion, where they were rated using the motor section of the Abnormal Involuntary Movements Scale (AIMS). The videotapes showed an average improvement of 3.4 points on the AIMS (out of 42 total), with improvements attributable to TBZ in 15 of the 19 participants (two had improved before taking TBZ, one did not change, and one did not return for re-evaluation). When participants were asked to subjectively report their condition, none reported a worsening of their symptoms. Only one participant reported more than mild side effects. For this person, akathisia (feelings of restlessness and urges to move about) improved when the dose was lowered. Before taking part in this study, 13 of the 19 participants had tried at least one medication for chorea that they reported to be ineffective. All of the participants who completed this study, however, decided to continue taking TBZ to treat their chorea. The researchers concluded that TBZ is effective and well-tolerated.
Huntington Study Group (HSG) and Prestwick Pharmaceuticals (2006) collaborated on a clinical trial involving TBZ called TETRA-HD. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD is a phase III clinical trial with the goal of determining the optimal dosage of TBZ in treating chorea and other involuntary movements 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. 54 of the participants were randomly assigned to receive TBZ 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 found that TBZ is effective in treating chorea and that its side effects 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 TBZ. Clinical assessments showed that TBZ 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 such as increased risk of suicide, must still be acknowledged. These results confirm the benefits of TBZ usage in ameliorating the symptoms of chorea.
When will TBZ be available in the US?^
On August 15, 2008 the Food and Drug Administration (FDA) approved the first treatment for HD in the United States when federal regulators cleared Xenazine, a form of tetrabenazine made by Prestwick Pharmaceuticals Inc., for treating chorea. Although Xenazine cannot cure HD and may have harmful side effects, the FDA approval will increase the number of treatment options available to HD patients.
A series of events led up to the approval of Xenazine. The results of the TETRA-HD study were reported in October 2004 and subsequently published in the reputable, peer-reviewed journal Neurology in 2006. In April 2005, Prestwick Pharmaceuticals, the manufacturers of TBZ, announced that they had filed a New Drug Application with the FDA. The approval of this application was not expected to take long because Prestwick was granted “fast track” and orphan drug status for TBZ by the FDA. Orphan drug status is given to drugs that treat diseases that affect fewer than 200,000 people in the U.S., and the companies that produce them receive additional incentives to get them to market. In December 2007 the FDA Advisory Committee unanimously recommended Xenazine to be approved, and in August 2008 it was officially approved.
For further reading^
- “FDA Approves First Drug for Treatment of Chorea in Huntington’s Disease” 15 Aug 2008. (http://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html) Press release from the FDA after Xenazine was approved in August 2008.
- “FDA Approves Tetrabenazine.” 17 Aug 2008. HD Lighthouse. ( http://hdlighthouse.org/showUpdate.php?p_articleNumber=589) An article from the HD Lighthouse contributing editor commenting on the FDA approval of tetrabenazine in August 2008.
- Huntington Study Group. “Tetrabenazine as Antichorea Therapy in Huntington Disease.” 2006. Neurology 66: 366-372 . This is the scientific article published by the Huntington Study Group discussing the TETRA-HD study and results.
- Mikkelsen, B.O. “Tolerance of tetrabenazine during long-term treatment.” 1983. ACTA Neurologica Scandinavica 68(1):57-60. This scientific article discusses side effects of tetrabenazine and explores the possibility of long-term use.
- Miller, Marsha. “FDA Approves Tetrabenazine.” 15 Aug 2008. Huntington’s Disease Society of America. A concise article from the HDSA summarizing key facts about tetrabenazine.
- Ondo, et al. “Tetrabenazine Treatment for Huntington’s Disease-Associated Chorea.” 2002. Clinical Neuropharmacology 25(6):300-302. This scientific article describes a study in which the efficacy in treating chorea and tolerability of tetrabenazine were tested on people with HD.
- Pearson, S.J. and Reynolds, G.P. “Depletion of monoamine transmitters by tetrabenazine in brain tissue in Huntington’s disease.” 1988. Neuropharmacology 27(7): 717-719. This scientific article describes a study done on brain tissue of people who had HD. It shows how those treated with tetrabenazine had reduced dopamine in their brains.
T. Wang, 2/6/09; recorded by B. Tatum, 8/21/12
Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening syndrome that can emerge in response to neuroleptic medications, such as tetrabenazine or deutetrabenazine. Neuroleptic medications, also known as antipsychotics, are broadly used to treat confusion and agitation and allow for normal movement. Symptoms of NMS include mental status change,…More
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
(as of October 2017)
SIGNAL is a Phase II trial that studies the safety, tolerability, and effectiveness of VX15, an antibody that aims to slow the impairments in cognition, movement and behavior in HD. VX15 is designed to deactivate a specific protein, semaphorin 4D (SEMA4D), that guides the activation and movement of cells. SEMA4D may be responsible for the inflammation that occurs in the brains of those with HD. Previous research suggests that VX15 may be able to block SEMA4D, reducing brain inflammation and slowing negative side effects. SIGNAL is a multi-center, randomized, double-blind placebo study at 20 sites in the US. They are seeking 116 people, ages 21 or older, who are either early in the progression of the disease or at risk for the disease. (For the most up to date information about SIGNAL, click here.)
Ongoing Studies that are No Longer Enrolling Participants
(as of October 2017)
First-HD and ARC-HD are Phase III clinical trials investigating the efficacy and safety of deutetrabenazine (SD-809) on HD patients who present with chorea. Deutetrabenazine has the same mechanism of action as the current treatment for chorea, tetrabenazine, however it is broken down much more slowly. The hope is that this slow release will allow the drug to deliver the same relief as tetrabenazine, with a lower daily dose and fewer side effects. The most common adverse side effects reported thus far, affecting ≥5% of participants, have been drowsiness, dry mouth, diarrhea, insomnia, and fatigue, though all these effects have been reported with tetrabenazine as well. While First-HD will establish the safety and effectiveness of deutetrabenazine, ARC-HD focuses on how switching to deutetrabenazine affects patients currently taking tetrabenazine to treat chorea. First-HD will last up to 4 months and ARC-HD will last up to 14 months. These studies are no longer enrolling participants. (For the most up to date information on these studies, click here).
LEGATO-HD is a Phase II clinical trial to investigate the efficacy and safety of laquinimod in the treatment of HD. Laquinimod is thought to decrease inflammatory responses that occur in the brain of HD patients. The primary metric for this study is change from baseline in the Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS) after 12 months of treatment with varying doses of laquinimod. Information regarding safety and side effects is also being collected. This study is sponsored by Teva Pharmaceuticals in collaboration with the Huntington Study Group (HSG) and European Huntington’s Disease Network (EHDN). This study is no longer enrolling participants. (For the most updated information on this study, click here).
PRIDE-HD is a Phase II randomized, double-blind clinical research study of the efficacy and safety of the drug pridopidine. Pridopidine is a dopamine stabilizer that can enhance or inhibit dopamine-controlled functions. For more information on the role dopamine plays in HD, click here. This study is investigating the effect pridopidine has on movement, thinking, and behavior in individuals with HD after 26 weeks of receiving the drug or placebo. This study is sponsored by Teva Pharmaceuticals in collaboration with Huntington Study Group (HSG) and European Huntington’s Disease Network (EHDN). 400 participants have been enrolled globally across 51 study sites. This study is no longer enrolling participants. (For the most up to date information on this study, click here).
Recently Completed Clinical Trials
(as of October 2017)
2CARE was a Phase III trial that aimed to study coenzyme Q10 as a potential treatment for HD. For more on coenzyme Q10, click here. The study aimed to measure the effectiveness of coenzyme Q10 in slowing the symptoms of HD and to study the long-term safety of administering the compound to HD patients. Previous studies have shown that coenzyme Q10 slightly slowed the progression of HD, but not enough to yield significant results. Compared to these previous studies, 2CARE used a much higher dosage for a longer time period. To date, it is the largest therapeutic clinical trial of HD, with enrollment of over 600 in the United States, Canada, and Australia. The study began in March of 2008 and was completed in July 2014. 2CARE was a double blind placebo study, in which participants were randomly assigned to one of two groups. The experimental treatment group received oral administration of coenzyme q10 in chewable form twice a day, for a total of 2400 mg/day. Researchers compared total functional capacity (TFC) scores, tolerability, adverse events, vital signs, and laboratory test results between the two groups. Results found that there were no statistically significant differences between treatment groups, leading the researchers to conclude that coenzyme Q10 is not a justified treatment option to slow functional decline in HD. (For more information on the results of 2CARE, click here.)
Creatine, Safety, Tolerability, & Efficacy in Huntington’s disease (CREST-E), conducted by The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester, was a Phase III clinical trial that aimed 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 HD-model mice supplemented with creatine displayed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. Participants in CREST-E were randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study was a large clinical trial, involving 46 research centers from around the world and enrolling around 550 participants. The study lasted 48 months and was completed in December of 2013. The results did not show statistically significant differences between the treatment and placebo groups. This study provided evidence that creatine is not beneficial for slowing functional decline in patients with early symptomatic HD. (For the most up to date information on this study, 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. Minocycline is an antibiotic that is primarily used to treat acne and other skin disorders. For more on minocycline, click here. The study is a Phase II clinical trial that was started in 2006 and completed in November 2008 by the Huntington Study Group (HSG) with funding by the FDA Office of Orphan Products Development. It was a double-blind 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 was abandoned. (For more about the results of the DOMINO study, click here.)
Pridopidine (ACR16), as described in the Pride-HD clinical study, is a dopamine stabilizer that can enhance or inhibit dopamine controlled functions. For more information on the role dopamine plays in HD, click here. The Huntington Study Group (HSG) conducted a Phase II clinical trial testing different doses of pridopidine on HD patients age 30 and older. HART was sponsored by NeuroSearch Sweden AB and was conducted in 27 research sites across North America. Previous studies showed that pridopidine 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 were randomly assigned to one of four groups: three experimental groups given different doses of pridopidine and a placebo group. The study occurred over the course of 12 weeks and was completed in May 2010. While there was no statistically significant treatment effect, the overall results suggest that pridopidine may be beneficial in improving motor function because patients in the highest dosage group (90 mg/day) displayed significant improvement in motor function as measured by the modified Motor Score (mMS). (For more on the HART study, click here.)
HORIZON was a Phase III clinical trial conducted by the Huntington Study Group 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 neurons 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 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. The study was ended early in April 2011 when the researchers discovered there were no statistically significant differences 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. (For more on the HORIZON study, click here.)
Early in 2009, the Huntington Study Group (HSG) received funding from the NIH to test the safety and tolerability of coenzyme-Q10 and remacemide hydrochloride in individuals who have tested positive for HD but do not yet show any motor symptoms. The study was called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials) and was a Phase II trial. The study was conducted at 23 clinical sites throughout the United States and was the first therapeutic research study in pre-manifest HD patients. Participants were randomly assigned to experimental groups receiving 600, 1200, and 2400 mg/day of coenzyme q10. At each dose, neither remacemide nor coenzyme Q10 produced significant slowing in functional decline in early HD. (For more on the PREQUEL study, click here.)
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), an omega-3 fatty acid commonly found in fish oil, slowed the progression of motor decline in HD patients. 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. This lack of improvement in both groups at 6 months yet improvement by 12 months of treatment could be explained by detection or attrition bias or chance but could also indicate that ethyl-EPA treatment may improve motor features in patients with HD over a longer treatment course. 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. (For more on the TREND-HD study, click here.)
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 on the TETRA-HD study, click here.)
For more information:
-L. Slang, 10-16-17
On the 19th of November, 2016, the University of California San Francisco’s Memory and Aging Center hosted their 13th Annual Huntington Disease Research Symposium. This symposium featured the latest in research and therapies, allowing patients and families more information about combating the disease. A recorded video of the symposium is available online at:
The symposium opened with Julia Kaye, PhD of the Finkbeiner Lab, based at the Gladstone Institute of Neurological Disease. Dr. Kaye presented her lab’s work on whole genome sequence analysis (WGSA,) which focuses on finding single nucleotide polymorphisms (SNPs) in HD patients. SNPs are small, single-letter changes in the structure of DNA that can drastically alter the functioning of a gene. The goal of this research was to find SNPs in HD patients that affect the progression and severity of the disease. This was achieved by observing pluripotent stem cells generated from patient skin samples, and how they fared when grown in the lab. Their survival was then correlated with data from WGSAs of the same patients, which were collected from blood samples. This research has promise for designating new targets for further study, but it is very early in development.
Lisa Ellerby, PhD from the Buck Institute for Research on Aging, presented next. Like the Finkbeiner Lab, Dr. Ellerby’s team is also attempting to discover targets for further study. Their work is centered around genetically correcting the Htt mutation in pluripotent stem cell lines derived from HD patients. While the ultimate goal in this research is to develop a therapy centered around transplanting corrected cells into the patient, for now Dr. Ellerby’s team is utilizing these cell lines to research a myriad of other therapeutic molecules and their potential in HD research.
Following Dr. Ellerby’s presentation, Vicki Wheelock, MD of the HDSA Center of Excellence at UC Davis presented her team’s findings from a novel lead-in study in HD. In earlier research, the protein BDNF (brain-derived neurotrophic factor) was discovered to promote the survival of striatal neurons and trigger the recruitment of new neurons, along with several other therapeutic effects. Levels of BDNF are found to be distinctly low in HD patients, marking the compound as a strong therapeutic candidate. Teams at UC Davis have since developed a line of bone marrow stem cells engineered to produce BDNF, tested these cells in mouse models, and developed a clinical protocol for testing this therapy in human patients. To test the effectiveness of a BDNF therapy in HD patients, a lead-in study was necessary to establish a baseline for HD progression. At this symposium, Dr. Wheelock presented her teams findings from such a study, designed to measure baseline differences between HD patients and the general population in a number of factors. This lead-in study lays the groundwork for future research not just on this protein, but for HD clinical research in general.
Alexandra Nelson, MD, PhD of the HDSA Center of Excellence at UCSF finished out the morning session with an overview of current clinical trials in HD. One of the drugs reviewed, Deutetrabenazine, has the capacity to become a more stable version of Tetrabenazine, a drug that manages some of the motor symptoms of HD. Other trials, like Signal-HD, seek to reduce brain inflammation, and slow down HD progression. Many of these new treatments are currently entering clinical safety trials, a promising and exciting step toward getting them into market.
The afternoon session of the symposium started off with a presentation by Kevin Barrows, an Integrative Medicine Physician. Dr. Barrows spoke of the benefits of practicing mindfulness to reduce the severity of some HD symptoms. Mindfulness therapy, which focuses on the intentional reflection and examination of one’s self, has been shown to have many benefits for HD patients, including decreased stress, anxiety, and depression, and increased bodily awareness. Dr. Barrows talked about mindfulness not only for HD patients, but also as a useful strategy for caregivers to take care of themselves.
Dr. Barrows presentation was followed by several breakout sessions, held two at a time. These presentations covered topics including staying active with HD, using music therapy to improve care for HD patients, managing difficult behaviors that arising from HD, and a brief overview of HD genetic counseling. The closing breakout session was a panel discussion with Natasha Boissier, LCSW, Andrea Zanko, MS, LCGC, and Alexandra Nelson, MD, PhD, focusing on how living with gratitude can improve the lives of HD patients.
The symposium brought members together from all over the HD community. Researchers, caretakers, therapists, patients, and their families were all involved in lending to the atmosphere the enthusiasm that permeated the event. In its 13th year the symposium continues to bring together patients and the researchers who fight for them, working together for hope.More
2016 HDSA Convention Summary Article
Strategies for Managing Depression in HD Families
Presentation Title: Strategies for Managing Depression
June 3, 2016
Dr. Karen Anderson, MD — Director of the HDSA Center of Excellence at Georgetown Hospital in Washington, D.C. and psychiatrist specializing in neuropsychiatry.
Panelists: Doris, Anne, and Cary — caretakers and members of the HD community who have been affected by depression.
The 2016 Annual Convention of the Huntington’s Disease Society of America (HDSA) took place in Baltimore, Maryland, from June 2–4, 2016. The HDSA Convention is the largest Huntington’s disease (HD) convention in the world and covers a combination of education, advocacy and research topics over the course of three days.
The purpose of this article is to summarize “Strategies for Managing Depression”, a presentation given at the 2016 HDSA Convention. To read more about the relationship between HD and depression, please visit this site.
This article will summarize the main points given in the presentation. It lasted a little over an hour, with 30 minutes allocated to Dr. Anderson’s presentation, 30 minutes for a panel on HD and depression, and 10 minutes for questions.
- Dr. Anderson’s Presentation (30 minutes)
Dr. Karen Anderson practices neuropsychiatry and is the director of the HDSA Center of Excellence at MedStar Georgetown University Hospital. At the start of her talk, Dr. Anderson disclosed that she has worked as a consultant and scientific advisor for Lundbeck and Teva pharmaceutical companies. She also stated that she has acted as a site investigator for several of their clinical trials, including SD809, a drug used for the treatment of chorea and referenced in this presentation. She was also on several scientific advisory panels for both pharmaceutical companies.
Dr. Anderson emphasized that the goal of her talk is to share information, not to give personal medical advice. The information should not be taken as a sole source of medical advice; instead, it should be discussed with one’s care team and clinicians.
Introduction and Symptoms of Depression in HD
In this section of the presentation, Dr. Anderson gave an overview of the relationship between depression and HD.
Causes and prevalence of depression in people with HD
Huntington’s disease affects the brain’s neurochemistry, which can lead to depression. Another factor that contributes to depression in HD patients is the loss of ability to do everyday things, such as driving, working, taking care of children, being independent, and maintaining continence. Losing the ability to do things once central to the identity of someone diagnosed with HD can often trigger depression. The recent loss of a loved one to HD or the anniversary of their death is also a common cause of depression. Additionally, the end of a treatment study can precipitate depression in study participants. For many people, the end of a clinical trial can represent the end of feeling proactive, and it is often unknown whether or not the trial made a difference in the progression of their disease. Centers doing clinical trials can mitigate this by staying in touch with patient participants and making sure participants are thanked and made aware of the impact they have made on HD research.
Many people experience depression and there are many reasons why someone, with or without HD, might experience depression. There are also several treatment options that have proven successful for HD patients who experience varying degrees of depression. As such, one of the last sections in this article focuses on treatment strategies such as psychotherapies, talk therapies, and medications.
In the brain, chemicals involved in reward, pleasure, and mood are affected by the progression of HD pathology. Depression can occur across all stages of HD, and even before someone starts experiencing motor control symptoms. Studies estimate that 20% to 80% of HD patients have depression at some point during their illness.
Depression often occurs in the early stages of HD. It can be concerning when someone in an HD family becomes depressed, since this is often thought to be a first sign of HD. Dr. Anderson advises her patients to seek treatment for depression when they are worried that it might be an early sign of HD. For someone at risk for HD, being treated for depression does not mean they will be diagnosed with HD.
Impact of depression on HD
Depression can have an impact on the progression of HD, which is a compelling reason to seek treatment. In fact, across neurological diseases, people who are depressed are found to have more negative outcomes. HD often progresses faster in people who are depressed. For example, depressed HD patients may experience greater memory decline, an inability to organize thoughts, lower quality of life, and decreased ability to care for oneself.
For people with HD and depression, the depression may worsen as the condition progresses. People can develop depression as they become aware of early symptoms of HD. Dr. Anderson reiterated that depression can worsen as patients start to lose the ability to perform everyday activities, or are told that they need to change how they perform certain activities in response to HD. Dr. Anderson expressed the importance of being aware of depression across all stages of HD.
Symptoms of Depression
Dr. Anderson outlined how she evaluates whether someone has depression. Psychiatrists ask about the following factors:
- Appetite changes
- Low mood, tearfulness
- Poor concentration
- Sleep changes
- Low energy
- Feelings of guilt
- Loss of interest in activities
- Loss of enjoyment
It is important to note that depression does not always manifest itself as sadness. It can appear as irritability, anger, anxiety, rumination, or resentment of caregivers. Depression can also take the form of a personality change.
A lot of people with HD experience sleep problems such as a flipped or erratic sleep schedule. They may also experience sleep fragmentation—this occurs when people sleep for a normal amount of time, but not well. Being fatigued can contribute to a low mood and a less cognitively aware state. For this reason, psychiatrists often look for underlying sleep issues that worsen depression symptoms.
Depression versus Apathy
Families and clinicians may confuse depression with apathy. About 50% of HD patients struggle with apathy or a general lack of motivation. Dr. Anderson expressed that the difference between depression and apathy matters because they require different treatment approaches. Depression can be treated with a combination of structured activity and medication. Apathy can be addressed with exercise and structured activity, but is harder to treat with medication.
It is also important to talk about apathy in order to educate families with HD. When someone has apathy, it’s hard for them to get started with an activity and they are less likely to be interested in doing things. Someone with apathy is not being stubborn. In fact, having a hard time with motivation is often a part of having HD.
Apathy can look like depression and sometimes there can be a combination of the two. Working with a psychiatrist can help tease out whether someone is experiencing depression, apathy, or a mix of both. Dr. Anderson noted that some antidepressants, such as SSRIs, are known to make apathy worse. A reduced dose or tapering off the antidepressant can sometimes help with this.
Non-pharmacological treatment strategies
Depression is very treatable, with or without drugs. Dr. Anderson emphasized that effective non-drug treatments are available. Some people do not respond to or tolerate antidepressants. They may experience side effects or may be unwilling to add another medication to their existing pill regimen. Some people might want to try counseling, either alone or in conjunction with medications.
If someone seems depressed, Dr. Anderson suggests increasing their activities and providing structure to their day. If exercise is a possibility, being physically active has been shown as helpful for mental health in general. Even a bit of walking or seated exercises with hand weights can alleviate depression.
In addition, if someone has lost a hobby due to HD, it can be helpful to re-frame hobbies in ways that the person is able to do. It is useful to consider how they can reclaim that activity. For example, if someone used to enjoy open water fishing, it is possible that they could try to fish while sitting on a platform.
Outdoor time is recommended to help with depression. Daylight exposure helps reset one’s internal clock and improves one’s mood. If it is not possible to be outside, sitting in a sunny room or getting out on the patio can make a difference.
Simply talking to someone supportive can alleviate depression. Supportive talk therapy can be helpful to address depression, isolation, or feelings of dependency, but the individual providing supportive conversation need not be an expert in HD. One type of therapy is called cognitive behavioral therapy. Patients are taught to catch negative feelings, then label and re-evaluate them. This type of therapy is practical, goal-oriented, and occurs over a few months.
To help with irritability, it is important to consider food intake. If a loved one is moody or cranky, it often helps to look at how much they are eating. People with HD need more calories than the average adult. If blood sugar gets too low, mood drops. Someone who is home by themselves should have a friend knock or call to remind them to have a snack and keep their blood sugar stable.
Lastly, Dr. Anderson talked about mindfulness as a way to cope with depression. Mindfulness is the process of paying attention on purpose, and without judgment, to the present moment. The goal is to reduce physical and emotional stress to make day-to-day life better. Being mindful involves being aware of experiences, rather than being consumed by them. Dr. Anderson discussed how mindfulness can help people make more purposeful choices instead of reacting automatically to things they cannot control. For example, at a family Thanksgiving that might be stressful or unpleasant, you can use mindfulness to ask yourself how you will experience the dinner in the best way possible.
Medication treatments for depression
Dr. Anderson talked about the different medication treatments for depression. As a psychiatrist, she considers potential side effects when deciding on a treatment course for each patient. The choice of treatment depends on the side effect profile for a particular individual.
When treating someone’s depression with medication, it’s important to keep in mind that the response to treatment is not always steady and is almost never immediate. Someone may get a bit better but then it may take more time to see further improvement.
Dr. Anderson provided the following list of antidepressants with reference to their side effects:
- Selective serotonin reuptake inhibitors (SSRIs). Options vary from more activating (such as paroxetine, fluoxetine, citalopram) to less sedating (sertraline).
- Vilazodone- SSRI and a 5-HT1A (serotonin) receptor partial agonist. This drug is thought to reduce sexual side effects.
- Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine. This class of drugs works well to treat anxiety, but they have cognitive effects and can cause people to feel tired and lethargic. If someone gets through initial treatment with these, they often do very well. But for someone concerned with how this might affect their thinking, this might not be the best drug to start with.
- This drug is activating and may worsen irritability, anxiety, and insomnia.
- This drug has noradrenergic and serotonergic activity. This drug is sedating and increases appetite. It is a good choice for someone who has trouble sleeping and gaining weight.
- These drugs have cognitive effects. People can feel lethargic or sedated, and they may gain weight.
Dr. Anderson discussed the concept of augmenting, or adding another drug (such as another antidepressant or mood stabilizer) to help the initial antidepressant work better. This can be done if the antidepressant is no longer working as well, or if it works well but not completely. Adding a drug from another class is preferable to increasing the dose of antidepressant, which might have side effects.
With antidepressants, patients take a pill for 4 to 6 weeks and often only start to feel a noticeable improvement about a month or more after starting to take the medication. It is often difficult to take a pill for a month or more before feeling a positive effect. Because the antidepressant has to be taken regularly, it is important to support people and encourage them to keep taking the medication until they feel better. In addition, when people start to feel better, they should keep taking the medication for 9 months or up to a year. If they stop too early, they could have a relapse, meaning the depression could come back and it could be harder to treat the second time. Some patients with a history of severe depression stay on medications more long-term.
Dr. Anderson made an important point about a drug called tetrabenazine (TBZ), used to treat chorea in HD patients. TBZ interferes with dopamine, serotonin, and norepinephrine in the brain. These important chemicals help us to be interested, have a good mood, and be engaged in life. They may appear at lower levels when someone is depressed. If depression or suicidal thinking occurs, TBZ should be reduced as it works by interfering with the very chemicals that naturally prevent depression.
In the HD community, suicide is a very important topic to talk about openly because people with HD are at greater risk of taking their own lives. It is estimated that suicide risk increases 4 to 7 times among HD patients compared to the rate of suicide in the general population. Changes in the brain can make people with HD more impulsive, which is a risk factor for suicide.
Dr. Anderson advised families to employ a strategy called “means reduction”, a way of reducing opportunities for impulsive attempts to commit self-harm. For example, gun owners can keep guns and bullets separated and locked up, or guns can be removed from the home altogether. In addition, family members can manage medications and only dispense daily doses.
For more information on suicidality in the HD community, please visit this site.
The presentation closed with a reiteration of how important it is to talk about depression is in the HD community, since the simple act of talking is a step towards helping people cope with depression.
- Panel with members of the HD community speaking about their experiences with depression (30 minutes)
Next, Dr. Anderson facilitated a panel discussion with Doris, Anne, and Cary, three women who spoke openly about their personal experiences with depression and HD. Dr. Anderson asked a series of questions listed below:
Question 1: What is it like when someone you love is depressed? How can you tell?
According to the panelists, when someone has depression, they often don’t want to get out of bed. If the caretaker is not there to get them out of the house, they may stay in bed all afternoon. They may feel a lack of motivation, energy, and initiative. In addition, they may talk less and appear more withdrawn.
Question 2: Have you tried any of the non-medication treatment strategies I discussed? Which ones have worked well for you?
Having an activity, a structured schedule, or something to look forward to makes a big difference! Walking or mild exercise improves mood.
Question 3: What do you do when someone is at work and can’t be there to provide structured activity?
That is definitely a difficult situation, and it is hard to have a good answer- it depends on the individual circumstance. Overall, finding small ways to make the person feel less stuck should be the priority. For example, engaging with their network of family, friends, and former coworkers could be helpful. Seeing people for coffee or lunch once a month can provide support.
Question 4: What have your experiences with antidepressants been like? How do you know if they are working? What does it look like when someone gets better from depression?
When someone is getting better from depression, they may start to seem more like their old self- for example, they may talk more, seem more energetic, or be more motivated to do activities.
Question 5: Have you found that people get better from depression slowly or not?
Based on the experiences of the panelists, it has been a slow and gradual improvement.
Question 6: Have there been setbacks or ups and downs when someone is getting better from depression?
Certainly with the disease in general, there are ups and downs.
Question 7: In your experience, what’s the difference between being depressed versus being discouraged by having this disease that affects so many different things?
People with Huntington’s disease can feel discouraged and sad, but depression is persistent and chronic. One of the panelists, when discussing her son who has HD, said: “There’s a sadness, but I don’t see the depression in him. He keeps going.” Another panelist added: “Projecting into the future makes everything hard- it’s a waste of energy. I have found that cognitive behavioral therapy helps. Catastrophizing your life does not go anywhere. It’s more practical to try and move your thought to a positive direction. But it took me 10 years to get to this point.”
A third panelist shared a thought brimming with hope: “I’m sixty now, long lived for an HD person. That makes me feel better.”
Resources and further reading
The recording of Dr. Anderson’s presentation: http://hdsa.org/about-hdsa/annual-convention/2016-convention/
Dr. Anderson’s presentation slides: http://hdsa.org/wp-content/uploads/2016/06/HDSA-2016-Anderson-Depression-Strategies-June-3rd.pdf
National 24/7 suicide hotlines:
On April 9th, HOPESters Natty and Caitlin attended Help4HD’s 3rd annual symposium in Sacramento, California. The all-day event featured a wide range of presentations from speakers representing academic institutions, pharmaceutical companies, and research groups. The event honored the work and retirement of Terry Tempkin, RNC, MSN, ANP. Terry is the Nurse Practitioner at the HDSA Center of Excellence, University of California, Davis Medical Center, and Department of Neurology. The event was attended by HD families, researchers, and advocates and was a full day of education for all.
Sponsors of the event included Raptor Pharmaceuticals, The Griffin Foundation, Teva Neuroscience, Ionis Pharmaceuticals, and Lundbeck Pharmaceuticals. Attending the symposium allowed HOPESters the opportunity to meet with others in the HD community working for therapeutics, a cure, and better patient advocacy for those affected by Huntington’s disease (HD). Below is a summary of each presentation from the day.
Dr. Jan Nolta, Ph.D., Director of UC Davis Stem Cell Program and UC Davis Institute for Regenerative Cures and Dr. Vicki Wheelock, MD, Director of the UC Davis Huntington’s Disease Clinic
“Bench to Bedside; Mesenchymal Stem/Stromal cells Engineered to Produce Brain-Derived Neurotrophic Factor as a Potential Treatment for Huntington’s Disease”
“Pre-Cell: The Path Forward and Findings Along the Way”
Dr. Nolta and Dr. Wheelock presented current updates on UC Davis’s progress in its HD stem cell treatment clinical trial. The proposed treatment uses mesenchymal stem cells (MSCs) engineered by Dr. Nolta and others at UC Davis in order to overproduce brain-derived neurotrophic factor (BDNF) as a therapeutic for HD. In HD, medium spinal neurons of the striatum die out, resulting in many of the symptoms seen in HD patients. Current research has identified lowered levels of BDNF as a key cause of this cell death as the mutant huntingtin protein blocks production of BDNF at the RNA level and reduces axonal transport from cortical cells to the striatum.
MSCs have been developed as a viable candidate for delivery of BDNF into the striatum due to their reliable safety profile and ease to engineer. Mouse models of HD treated with implantation of these engineered MSCs have showed success in decreasing behavioral symptoms such as anxiety and reduced striatal atrophy. Mouse models have also revealed key information about the effectiveness of different dosages of MSC-delivered BDNF. Mouse model studies also showed an extended life span and increased neurogenesis, or production of new neurons, in mice treated with MSC-delivered BDNF. Please see this HOPES article on the UC Davis team’s research. The group at UC Davis has completed the first phase of their project plan, “Pre-Cell”, and are working to prove that delivery of MSCs can be done safely in larger mammals in order to receive approval for the first in-human trial of gene therapy engineered MSCs implanted into the brains of patients with Huntington’s disease. The most recent publication on this research is available here.
Jimmy Pollard, CHDI Foundation
“You Are a Part of the Change — Patient Participation in Clinical Trials”
Jimmy Pollard, HD health educator and advocate, spoke about the origins of Huntington’s disease, specifically with regards to its discovery by Dr. Huntington. However Jimmy spent the majority of his presentation taking about the value of HD families in accelerating research and education around HD. One example he gave was the advocacy work of Marjorie Guthrie when she discovered that her husband Woody Guthrie, renowned folk singer, was afflicted with HD. In addition to starting the Committee to Combat Huntington’s Disease, which eventually became the Huntington’s Disease Society of America, Marjorie Guthrie was also instrumental in the creation of the World Federation of Neurology’s Research Commission of Huntington’s chorea (as it was called at the time).
Jimmy also emphasized the value that sharing of stories, such as those in Life Interrupted, has for HD awareness efforts. Finally, he emphasized and thanked everyone in the room who had ever contributed to a clinical trial on HD, acknowledging the necessity and sacrifice of those who constantly supported research efforts.
Morning Panel: Update on Clinical Trials and Studies in HD
Dr. Victor Abler, Global Medical Director at Teva Pharmaceuticals
Dr. Abler described three current clinical trials that Teva Pharmaceuticals is conducting. The first is Pride-HD, which is a Phase II, double blind, randomized control trial testing the impact of pridopidine on motor impairment in patients with Huntington’s disease. Pride-HD is primarily aimed at testing the safety and efficacy of pridopidine at different dosages compared to placebo controls. This study is closed for enrollment but continuing through September of 2016.
The second trial presented was data from First-HD and ARC-HD, the former of which has been completed and the latter of which has completed enrollment but is still underway. These Phase III studies evaluated the safety and effectiveness of SD-809 (deutetrabenazine) in the treatment of chorea. Results have been positive with transition from tetrabenazine, the current treatment for chorea. The most common adverse side effects, affecting ≥5% of participants, were drowsiness, dry mouth, diarrhea, insomnia, and fatigue. SD-809 was granted Orphan Drug Designation for treatment of HD by the FDA in 2015.
The final trial presented was LEGATO-HD, a Phase II study to study the efficacy and safety of laquinimod in the treatment of HD. Laquinimod is understood to decrease inflammatory responses that occur in the brain of someone with HD. The primary endpoint for this study is measurement of a change from baseline in the Unified Huntington’s Disease Rating Scale- Total Motor Score (UHDRS-TMS) after 12 months of treatment. This study is currently enrolling.
Dr. Ben Cadieux, Senior Director of Clinical Development at Raptor Pharmaceuticals
Dr. Ben Cadieux discussed the investigation of RP-103 by Raptor Pharmaceuticals for the treatment of HD. The current Phase II/III trial is building on previous safety trials as well as findings that RP-103 is able to have effects on glucose metabolism, oxidative stress, and brain-derived neurotropic factor (BDNF) production, all of which are abnormal in the brains of those with HD. Measurements of effectiveness on the UHDRS-TFC and Independence Scale showed mild improvements over time in those taking RP-103 compared to controls. Following this Phase II/III trial, the next steps for Raptor are to continue analyzing the data for effectiveness and long-term safety and to develop a stage III protocol.
Dr. Peg Nopoulus, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Dr. Nopoulus presented her team’s work on the Kids HD and Kids JHD programs. The Kids HD study is a longitudinal study of children, adolescents, and young adults who are at-risk for HD. The goal of this research is to identify early changes in brain structure and development in those that are gene-expanded (GE) and will eventually develop HD compared to their gene non-expanded (GNE) counterparts in the at-risk population. In order to study brain structure and development changes, researchers measure brain structure and function as well as behavioral, motor, and cognitive abilities over time. To separate out the control, or NGE, individuals, researchers also conduct genetic testing of patients to determine their HD gene status, but due to the ethical implications of such information about minors, all information is deidentified.
Results thus far have shown reduced striatal volumes in those individuals that are gene-expanded in comparison to those that are gene non-expanded. As a longitudinal study, Kids-HD is still recruiting and is based out of the University of Iowa.
The Kids-JHD study overlaps with the Kids-HD study in most measurement endpoints, including brain volumes, cognitive and motor abilities. However, due to the current lack of significant research on JHD, Kids-JHD also aims to better understand the brain changes that occur in juvenile-onset, as opposed to adult-onset, of HD. In addition, the Kids-JHD program includes an extra day of clinical assessment conducted by a team of doctors who are experts in JHD. The team is able to assess, and if needed, make recommendations to parents and other physicians for the care of individuals with JHD. Reports with relevant information on the child’s clinical status and abilities are sent to local doctors and schools to help inform those involved in the child’s care and development.
Please see clinicaltrials.gov or this HDSA resource to find up to date information on clinical trials.
Kyle Fink, Ph.D. Post-Doctoral Fellow at the UC Davis Institute for Regenerative
Gene Therapy in JHD
Dr. Fink presented his research on the potential for gene modification using transcription-like effectors (TALES) as a treatment for JHD. The idea behind this research is to get to the root of the problem, the expanded CAG repeats in the Huntingtin gene, that result in production of mutant protein in those with HD. Targeting protein levels is an option but that would require the continuous administration of a drug to keep huntingtin protein levels low. Dr. Fink’s work uses TALES to target single-nucleotide polymorphisms (SNPs), or specific targets in the DNA and cause collapse of the CAG repeat extension or repression of the mutant gene. The collapse model works by using two TALES that target unique SNPS around the CAG repeat extension and cause shortening of the DNA until they reach a certain distance from each other (approximately 16-18 CAG repeats), and are no longer able to function. This results in a mutant HTT gene being shortened to one that has a normal CAG repeat length. TALES can also be used for gene silencing, another approach being investigated. When these TALES are used in patient fibroblasts (skin cells), researchers found a markedly reduced amount of mutant huntingtin protein. They also found a 20% reduction in the amount of RNA production, the precursor to the huntingtin protein. These experiments were also done in primary neuron cultures of transgenic mice, with similar results.
The main limitation to complete silencing or shortening of the mutant HTT gene seem to be delivery into the cells. Current research efforts and collaborations are focused on the development of various delivery options, including viral vectors, synthetic nanoparticles, or mesenchymal stem cells. This research is still in early stages, working in vitro with human cells and mice, but researchers hope to be able to progress to treatment of the striatum and cerebellum of mice.
Dr. Peg Napolous, Professor of Psychiatry, Pediatrics, and Neurology at The University of Iowa, Kids HD and Kids JHD Research Director
Psychiatric Aspects of Huntington’s Disease
Dr. Napolous discussed the extended and varied presentation of psychiatric symptoms in individuals with Huntington’s disease. Extended information on this topic is available here. Dr. Napolous emphasized the importance of understanding psychiatric and behavioral symptoms of HD because they typically appear years before motor symptoms do and early identification is important for the care of an individual both emotionally and medically. In addition, many of the psychiatric and behavioral symptoms are treatable with medications used for other disorders. Treatments for HD symptoms are not curative, but rather symptom management. For some aspects of the disease, such as cognitive abilities, apathy, and issues with balance, speech, and swallowing— currently available medications are minimally effective. However, for symptoms such as chorea, irritability, and depression, treatments can be very effective. Finally, Dr. Napolous emphasized the importance of having a team of care providers that can meet the unique needs of the HD patient and family.
Hurry Up and Wait
To conclude the conference, Jimmy Pollard engaged attendees with a presentation that worked to help build an understanding for the experience of HD. This session included an explanation of the ways in which thinking can be affected in those with HD, such as memory impairment, slower thinking, and difficulty focusing, organizing, and planning. One activity Jimmy had attendees do was to attempt to write their names at a rate of one letter every ten seconds and pay attention to the feelings that arose when they were not able to act more quickly. Participants described the task as frustrating, agitating, and tiring; they also noted that they were easily distracted when forced to move at such a pace. Another activity focused on HD patients’ typical dislike of surprises because of the increased difficulty it adds to their ability to plan. A participant was blindfolded and then told to find an item a few tables away. However, when she was close to her destination, Jimmy spun her around in several circles to cause disorientation. This ‘surprise’ of being spun around, was meant to mirror the way in which HD patients feel when something in their day is not the way the have come to expect it. Finally, Jimmy ended on one take home message, which was to “hurry up and wait”. A seemingly contradictory statement, Jimmy hoped to emphasize to attendees that the various cognitive effects of HD are complicated, and patients are often impatient with themselves and the world around them, especially when they are forced to function at a much slower pace than they want. As someone caring for, or interacting with, an individual with HD, it is important to be aware of their array of emotions and experiences and ‘hurry up’ when they need you to, but to ‘wait’ for them as well. Jimmy’s full presentation is available here.
Madam Secretary; Season 2, Episode 6; Catch and Release
Madam Secretary is a fictional television drama that follows the work of Elizabeth McCord, the United States’ Secretary of State. In this particular episode, the State Department learns that a new leader of ISIS has released a video showing the beheading of an American aid worker. After some research into the “Jihadi Judd” character who committed the act, Secretary McCord learns that not only is this leader an American, but the son of a State Department Secretary employee, Judith Fanning.
Secretary McCord calls Judith Fanning into her office after learning that her son, Adam Fanning, grew up in Cairo and learned Arabic in an American international school. During his time in college, he became radicalized. The mother claims that she has not been in contact with her son for over a year and begs the Secretary for his safe return.
However, after further research, Secretary McCord realizes that there is more to the story.
Nadine [State Department Employee]: The husband’s death complicates things.
Secretary McCord: How? I thought it was a car accident?
Nadine: I remembered the circumstances when I reviewed her file. He lost control of the car due to a seizure caused by Huntington’s disease. He was barely 43 years old and he had been misdiagnosed for almost two years. My understanding is that she blames herself for not catching it sooner.
Secretary McCord: This is a morbid detail to note.
Nadine: Too morbid?
Secretary McCord: No, I think you might actually be on to something.
Upon learning that Adam Fanning’s father had Huntington’s disease, Secretary McCord knows Judith Fanning is hiding something. Furthermore, it is discovered that Judith Fanning contacted her son within the last six months and had sent thousands of dollars to the Middle East for the purchase of a drug called Tetrabenazine. Secretary McCord decides to question Judith Fanning in person one more time.
Judith Fanning: I didn’t realize you’d be the closer.
Secretary McCord: When my own employee lies to my face, I like to find out why.
Judith Fanning: I can’t help you. You want to kill my son.
Secretary McCord: I want to stop him from killing innocent people. You should too.
Judith Fanning: I want my son back, the way that he was.
Secretary McCord: Before he became radicalized. Before you found out he had Huntington’s disease. Early onset sufferers are likely to have children who exhibit symptoms even earlier. Is that what happened to Adam?
Judith Fanning: Last year, he e-mailed me that he wanted to talk about his father’s symptoms so we Skyped. And there he was, he was shaking like a leaf.
Secretary McCord: Did he say where he was or who he’d been with?
Judith Fanning: Nothing. I told you, I will be of no help.
Secretary McCord: Your computer records show shortly before you sent the money, you searched online for information on a drug, Tetrabenazine. It’s the only medicine proven to help with early onset spasms. It’s what the money was for, wasn’t it?
Judith Fanning: I know what Adam did was unforgivable. He’s still my son. Promise me that you’ll give him a chance, promise that you won’t kill him.
Secretary McCord: I’m sorry.
Later to her assistant:
Secretary McCord: Get any traces of Tetrabenazine crossing ISIS territory…make it clear that no one outside our inner circle knows why we’re looking into it.
During the rest of the episode, we witness Secretary McCord’s thought process as she tries to figure out how to stop Adam Fanning from killing more innocent Americans. Through a conversation with her brother, Secretary McCord learns that a courier is transporting large orders of Tetrabenazine, a prescription medicine that reduces motor spasms and uncontrolled movements, across ISIS territory to Adam Fanning. After verifying the courier and Adam Fanning’s identity, Secretary McCord watches over video surveillance as President Dalton issues the order to kill both the courier and Adam Fanning through a drone strike.
This episode of Madam Secretary does an accurate job describing Huntington’s disease. Judith Fanning knows that her son is symptomatic with the disease, as demonstrated from the tremors she sees from a Skype video call. Since Adam Fanning is in his early 20’s, it is likely that he has Juvenile Huntington’s disease. However, a genetic testing would be needed to determine his CAG count. If it is over 38 repeats, it indicates the presence of Huntington’s disease.
Furthermore, Tetrabenazine is currently the only FDA approved drug on the market for Huntington’s disease. It reduces occurrences of chorea and other symptoms that result from motor control. Secretary McCord notes that early sufferers often have children with early onset as well. While there is correlative evidence that this may be true, one cannot make a causal claim that all early onset sufferers will have symptomatic children with similar age of onset due to genetic variations during reproduction.
Overall, this episode does an accurate job of reflecting the medical science and treatments of Huntington’s disease, albeit in an unfortunate scenario involving issues of national security.
K Powers 2016
Following her great success with Still Alice and Alzheimer’s disease, neuroscientist and author Lisa Genova attempts to accurately portray the disease experience of a Huntington’s disease (HD) family in her latest novel, Inside the O’Briens.
Unlike most media outlets, Genova goes to great lengths to understand the disease, both medically and socially, through interviews with HD researchers, clinicians and family members. Whether it’s describing the deterioration of the disease or explaining job discrimination, Genova succeeds in portraying the real HD disease experience.
Inside the O’Briens follows the story of Joe O’Brien, a middle age Boston police officer. He is married to Rosie O’Brien, with whom he has four children: Patrick, JJ, Meghan and Katie, all of whom still reside in the same triple-decker house in Charlestown, Massachusetts. Joe lives a content life and has very little problems within his family, despite a stressful job as an active duty police officer.
However, Joe and his family begin to notice changes in his behavior and movements. Joe is quick to anger and begins to loose his coordination. His wife, Rosie, convinces Joe to seek medical help. Sadly, he is diagnosed with Huntington’s disease. This news comes to a shock for Joe, whose family never acknowledged a history of the disease, until he re-considered the symptoms of his mother’s “alcoholism” many decades ago.
The story outlines the challenges Joe’s family must face as they not only navigate the disease progression of their father, but the fact that all four siblings have a 50% chance of inheriting the disease. The book is a challenging read, accurately portraying the unique problems HD families all over the world face.
Genetic testing, in addition to reproductive strategies, is one of the most controversial aspects of the HD experience. Despite the presence of a gene test, estimates show only 5-10% of all at-risk individuals choose to undergo predictive genetic testing (Oster et al., 2011 ). These statistics sometimes frustrate clinicians, leading to rash or coerced genetic testing decisions between the patient and doctor.
Rosie, Joe’s wife, accompanies Joe on a consultation with neurologist Dr. Hagler. Rosie notes the various movement symptoms Joe does not notice due to a lack of proprioception, or the ability to detect one’s body position. Dr. Hagler requests information regarding Joe’s family history and discovers that his mother was hospitalized for “alcoholism.” She also has Joe perform several neurological tests without explaining the reasoning behind these tests. Despite Joe’s insistence that he is just having a knee problem, Dr. Hagler suddenly diagnoses Joe with Huntington’s disease, but admits they should get an MRI and genetic testing to confirm her diagnosis (76-108).
Without any consent or transparency, Dr. Hagler diagnoses Joe with a devastating neurological disease with no counseling or explanation, causing great psychological stress to the family. Joe is furious that a medical professional could be so irresponsible in her prognosis:
“Huntington’s. It’s pure malarkey, and Joe won’t give it any stock. Police officers deal in facts, not speculation, and the fact is, this doctor threw out this big, scary medical word without having done any real medical tests, without knowing a damn thing. It was an offhand, irresponsible remark. It’s practically malpractice, to put a word like that out there, into their innocent heads, with no facts to back it up. It’s complete bullshit is what it is” (84).
Genova does an excellent job of highlighting the ways in which professionals can negatively impact a diagnosis experience. For families unaware of a history of Huntington’s disease, an abrupt clinical diagnosis with little explanation or consent can be harmful.
Furthermore, a diagnosis of Huntington’s disease can be devastating because of the implications it can have for younger generations. In the case of Joe’s family, his diagnosis means that his four children also must acknowledge they each have a 50% chance of inheriting the disease.
Genova highlights the tensions this statistic can cause among family members, especially when it comes to making the decision to test. In one section of the book, Genova creates a dialogue between the four siblings regarding their decision to test. The brothers, JJ and Patrick, are frustrated by the fact that they must undergo a long genetic testing process to find out if they have inherited the disease. Patrick refuses to get tested as he does not want to do any of the counseling.
JJ decides to test as his wife, Colleen, is pregnant with their first child. Meghan, one of the sisters, asks JJ if he and Colleen would have an abortion if he tested positive for the disease and so did the baby. [For more information on fetal testing or family planning in general, click here.] The stress is palpable. JJ doesn’t have an answer to his sister’s question.
The siblings discuss the fear that they’ve already started exhibiting symptoms. Meg, a ballet dancer, believes she’s messing up more in her routines. It is not unusual for those at risk to self-identify or diagnose based off behaviors that may or may not be related to Huntington’s disease. Her siblings try to reassure her that it is nothing.
At the end of the conversation, JJ and Meg decide to pursue testing, Patrick will not, and the youngest, Kate, is undecided.
Kate decides to pursue the genetic counseling process. She meets with Eric Clarkson, a genetic counselor. She does so after an upsetting neurological exam by Dr. Hagler, the same woman that analyzed Kate’s father’s movements. At the end of the exam, Dr. Hagler tells Kate that everything looks normal, leaving Kate with mixed emotions. She’s spent the last few weeks studying herself, trying to identify signs of the disease. Now she can finally stop. In Kate’s words: “That neuro exam was like surviving fifteen rounds in a boxing ring. She’s been declared the winner, but she still got knocked around” (162).
Eric takes over for Dr. Hagler to discuss genetic testing with Kate, asking her about the uncertainty surrounding her decision to test. Katie admits to Eric that she believes she has the gene because she looks like her dad’s mother. Eric reassures her that physical resemblance has nothing to do with HD inheritance. He uses this misconception as an opportunity to go over basic genetics, explaining DNA, chromosomes, and genes.
Additionally, Eric asks Kate to articulate what life would be like if she tested negative (“biggest relief ever”) and if she tested positive, along with her siblings testing positive. Kate says she “wouldn’t jump off the Tobin [bridge]” (168). Kate is getting increasingly uncomfortable with the intensity of the conversation. She grows increasingly impatient and tries to ascertain the reason for this “interrogation.”
Eric explains to her that he will not deny her the test. However, he says, “we want you to understand what you’re getting into and have the tools to deal with it. We feel responsibility for how you’re going to react” (171). He says that Kate can come back in two weeks to get the test or continue to visit with each other until she feels ready. He emphasizes that he will deliver her results to her in-person, and not over the telephone, a common best practice of genetic testing.
Overall, Eric Clarkson does an excellent job explaining the disease to Kate, as well as the emotional implications of genetic testing.
Family Members with HD
Many children from Huntington’s disease families must reconcile the fact that they have watched a parent suffer from a long, debilitating illness. This experience can cause trauma and psychological stress, especially as many of these children must also face their own personal realities of the disease.
Joe is no exception:
“But while he’s been doing his best to avoid falling down the dark, muddy rabbit hole of Huntington’s disease, he has been thinking a lot about his mother. Joe stops turning the screwdriver and runs his index finger over the scar by the outside corner of his left eye…His mother threw a potato masher across the room…Joe likes to believe that the scar by his eye is the only thing he got from his mother, a single souvenir of her madness” (85).
The disease can often strip individuals of their identities as well:
“The woman in that bed would never be able to read or sing or smile at him again. The woman in that bed was nobody’s mother” (87).
Grappling with Huntington’s disease can be a taxing feat considering the fact that multiple generations often have to deal with its consequences simultaneously. This burden is particularly evident when Joe must tell his children that they all have a 50% chance of inheriting the disease, in addition to the risk it poses to any children they plan on having. As described on page 122, the four siblings have great difficulty comprehending the magnitude of the situation. For JJ and his wife Colleen, it is far too real, as they reveal that Colleen is pregnant.
As is revealed later in the text, JJ tests positive for the faulty gene, meaning his child is now also at-risk for the disease. He and Colleen decide to keep the baby, despite the risk. As stated on page 202, “Joe prays everyday that the baby is healthy.” Joe also acknowledges that once the baby is born, the child cannot be tested until he or she makes the decision to do so, which at minimum is 18 years away, meaning he may never know whether or not it passes on to the next generation.
Unemployment is perhaps one of the most difficult transitions for many HD patients living in their working prime. Joe, a police officer, must face this transition earlier than others due to the high intensity and dangers involved in his job. Before losing his position on the force, Joe is accused of directing traffic while drunk, a common misconception of individuals with HD. He had not yet revealed his diagnosis to anyone outside his closest circles. However, after several complaints and rumors, Joe must finally disclose his disease status to his boss. Joe must grapple with the fact that, at best, he may keep his job at a desk. Otherwise, his future on the force does not look promising (234).
Genova uses this crisis in Joe’s life to explain the Genetic Information Non-Discrimination Act (GINA). This piece of legislation “makes it illegal for employers to terminate an employee based on genetic information” (247). However, an employer retains the right to fire somebody if that individual poses a safety threat or cannot do his or her job effectively. This caveat means Joe cannot be protected by GINA, but perhaps this information can help other readers.
Suicidal ideation is one of the most pressing issues in the Huntington’s disease community. It is a difficult topic to discuss, but a matter that must be addressed in order to make progress and educate communities touched by the disease.
When Joe is accused of drunk policing, his co-worker mentions that “this time of year is brutal” (244). The community has seen three suicides in the month of January. Joe imagines the various ways these individuals may have killed themselves. The last one he imagines: “a cop eats his gun” (244). He then thinks this “last one is how he’d do it, if suicide were his plan.”
Joe spends several scenes of the book contemplating his death. Chapter 29 begins with the sentence, “The gun is still his plan.” Rosie dissuaded Joe from taking his own life before, but his ideation is still frequent. Joe finds himself obsessively checking his draw for the gun, just in case he decides he needs to use it. Katie, his youngest, is the one that has the most effective impact on Joe leaving his “perfect plan behind.”
The passage reads as follows:
“’We don’t know anyone else with HD. You’re the only example we have. We are going to learn how to live and die with HD from you, Dad’…
It’s the perfect plan. He’ll be teaching them the human thing to do, the victorious way out. The gun. He should check the gun” (273).
Through his conversation with Kate, Joe realizes the importance of his presence to his family. He decides that, personally, it would be better for him to not choose suicide.
While suicide and job loss often grab the headlines for HD communities, sometimes the everyday challenges are the hardest.
Joe describes his everyday encounter with strangers. Due to a lack of proprioception, or the ability to sense one’s body position, Joe can only perceive his movements “through the mirror of the guarded, unforgiving stares of strangers” (212). Otherwise, he cannot tell that his body is moving. Joe describes the feeling of having strangers stare at him, trying to pin him into categories like drunk, mentally impaired, harmless, violent, deranged. As Joe states, he is “horrifying, unacceptable, and then invisible” to these strangers.
Furthermore, Joe explains his symptoms by calling himself his own “stuntman.” With the combination of proprioception and anosognosia, he is unaware of the placement of his body. Not only does this cause him to move unexpectedly, but often with more force than intended. He also finds himself hard pressed to control extreme mood swings, often towards anger, which often makes him feel guilty as it can be extremely traumatizing for his family.
Joe also describes his challenges with the limited number of drugs on the market. While Tetrabenazine helps control his chorea, Joe must take less of it as it increases his suicidal ideation. The constant management of drugs to control for various symptoms of HD can be exhausting.
One of the greatest mechanisms for coping with the daily challenges with the disease is a support system. When Joe attends a baseball game with his friends, he must face the unforgiving glares of strangers bewildered by his movements. However, his friends and family are there to support him, melting away the attempts of others to judge him. As the Red Sox win the game, Joe “takes a moment, wanting to remember this, the joy of the win, the beers and pizza, the electric energy of the crowd, a night at Fenway with his best friends and his two sons. His seat ain’t empty yet. And tonight, he enjoyed every wicked awesome second of it” (330).
Lisa Genova provides readers with one of the most comprehensive looks into the lives of those affected by Huntington’s disease. She touches on issues like Juvenile Huntington’s disease, insurance, genetic testing, drugs, and more, all the while providing and engaging story for readers from all walks of life. Genova does an excellent job proving she did her research. Whether it was speaking with HD families, connecting with the Huntington’s Disease Society of America or grilling HD researchers, she makes every effort to accurately portray one potential disease experience at both the family and the individual level.
For Future Reading
Oster, Emily, Ira Shoulson, and E. Dorsey. Optimal expectations and limited medical testing: evidence from Huntington disease. No. w17629. National Bureau of Economic Research, 2011.
In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.
The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.
The last day of the conference focused on various therapies, life habits, and treatment options. Each talk was presented by a different scientist.
Management of Behavioral Problems in HD (David Craufurd, United Kingdom)
Behavioral problems have a large effect on the quality of life for an HD patient. They may include depression, suicide, anxiety, agitation, irritability, impulsive aggressive, apathy, perseveration, psychotic symptoms, disturbed sleep patterns, and OCD; the most common symptoms are fatigue and lack of initiative or perseverance. Often, these symptoms can become more distressing than the cognitive and motor symptoms. While cognitive and psychological symptoms have a far greater impact on Functional Capacity, both sets of symptoms respond to treatments and medications available now.
Dr. Craufurd explained that depression and irritability remain at relatively equal levels throughout different stages, but anxiety is often more prevalent in late-stage HD. Treatments vary from person to person. Depression in HD patients often responds well to conventional antidepressant medication. Selective serotonin reuptake inhibitors, at higher doses, can be helpful for irritability. Physicians and other medical professionals must be aware that relapse often occurs when treatment stops. In addition to medication, general psychiatric support is needed, making a great argument for beginning cognitive behavioral therapy during early stages of the disease.
Treatment of apathy is not always pharmological, but rather, it requires psychoeducation within structured environments such as adult day care and exercise programs. Physicians should avoid the use of dopamine blocking or depleting drugs in excess as neuroleptics and tetrabenazine might worsen apathy.
One should always consult their medical professional before beginning any course of medical treatment.
Deep Brain Stimulation in HD (Binit Shah, USA)
Many HD patients experience a symptom set known as chorea, a random, involuntary arrhythmic set of movements of the face, trunk, and limbs. Chorea is thought to be a loss of striatal GABAergic inhibitory projections to the Globus pallidus externa. While pharmalogical treatments such as tetrabenazine exist, surgical treatment for chorea has become available in recent years.
Surgery to treat chorea often involves making legions in the pallidum of the brain, known as a pallidotomy. During this procedure, an electrode is inserted into the brain, heated up, and then used to target specific nuclei. The other form of brains surgery, deep brain stimulation, uses electrical fields to attack its targets. Results essentially decrease inhibition of indirect pathways, which lead to the trademark excessive moments.
Deep Brain Stimulation (DBS) is a surgical implantation of electrodes into deep brain structures while patent is awake. Connection and implementation of a pulse generator occur under general anesthesia.
As with any brain surgery, there are certainly risks, as well as candidacy factors. While DBS and pallidotomies can have immediate results, a “honeymoon effect” can occur, in which results are not long lasting. To be a candidate for this type of surgery, one must express appropriate motor symptoms that are less prominent than ataxia or dystonia. The patient cannot have severe impairments to cognitive or physiological functions as the patient must be actively engaged in the operating room and programming period. It is unclear whether these procedures are associated with adverse cognitive effects. While DBS and pallidotomy can provide some relief, it has no impact on the slowing or stopping of the progression of Huntington’s disease. Other motor features will still express and cognitive/psychological symptoms can predominate. Unfortunately, it is costly as well and is not covered by many insurance plans.
Swallowing and Nutrition (Francis Walker,US)
Huntington’s disease creates a metabolic inefficiency within an individual’s body. While appetite, food consumption and energy consumption increase in HD, weight loss is often present. Weight loss, especially in late stages, is often due to swallowing and increased movements. As for earlier stages, the causes are unclear. However, increased CAG length is associated with lower weight in HD patients.
Many problems arise with swallowing. Mylohyoid and geniohyoid muscle contractions within the throat are erratic and uncontrollable. This can lead to a delay in swallowing, retention of food in the mouth, incomplete or repeated swallows, and a lack of coordination between speaking, swallowing, and breathing. Additionally, impulsivity and eating too fast cause choking hazards. Chorea and impersistence of the tongue and pharynx result in a spillage of food.
Signs of trouble swallowing include repeated throat clearing, coughing, “wet mouth” speaking tones, progressive slowing of feeding, regurgitation, and congestion.
There are certain methodologies that can be used to ease difficulties associated with eating. In the early stages of the disease, avoid excessive eating. If weight loss is prominent, physicians should look for signs of gastritis or depression. During mid-stages, develop strategies to slow down and create smaller portions. Increased calories within meals as well as regular meal routines can help. In late stages, high-fat meals are essential for calories.
Below is a list of other tips and hints for caregivers responsible for HD patients’ meals:
• Use gravy sauces or condiments with dry foods.
• Crush medications in apple sauce.
• Avoid distractions and talking while eating.
• Learn the Heimlich maneuver.
• Place food on the back of the molars if the patient has trouble maneuvering food within the mouth.
• Use thickened liquids.
• If gurgling or wet sounds occur, ask the patient to cough.
• Make sure food is swallowed. Try swallowing twice, if needed.
Late stage treatment options and wishes in relation to quality of life (Raymund Roos, Netherlands)
End-of-life treatments and plans can be difficult for families to think about, let alone plan. HD patients face a variety of dilemmas such as pneumonia, the decision to insert a feeding tube, use of deep sedation, and even, at times, physician assisted suicide or euthanasia.
The most common causes of death for HD patients include pneumonia, choking, suicide and euthanasia. It is important for medical professionals to understand the challenges their patients face and, if applicable, in their state or country, know the options and procedures if the patient requests death with dignity. The criteria for ending life include 1) voluntary participation, 2) suffering unbearably without relief, 3) a physician must have informed knowledge of the situation, 4) no reasonable or alternative solution exists, and 5) the procedure is performed professionally and carefully.
Dr. Raymund Ross conducted a survey study in the Netherlands, where the Termination of Life and Request and Assisted Suicide Act legalizes euthanasia under strict conditions. The aim of the study was to determine whether there were any end-of-life wishes present in Dutch HD patients. Furthermore, he attempted to understand if certain disease characteristics contributed to these wishes.
75% of survey participants indicated that they had thoughts about end-of-life alternatives due to the loss of their personal dignity. Often these patients had been exposed to family members who had suffered an earlier fate, which influences the patient’s decision as he/she understands the disease progression.
Dr. Raymund Ross explored the results of discussion of euthanasia with patients, which often decreased the amount of follow-through from the patient. He also encouraged physicians to take initiative to talk to patients about end-of-life matters early on, as to not complicate matters for their caregivers when the patient can no longer make decisions for his or herself.
1. “Hereditary Disease Foundation – Predictive Test Guidelines.” Hereditary Disease Foundation. N.p., n.d. Web. 17 Jan. 2014. .
2. Semaka, A., L. Balneaves, and M. Hayden. “”Grasping the Grey”: Patient Understanding and Interpretation of an Intermediate Allele Predictive Test Result for Huntington Disease.” Journal of Genetic Testing (2013): 200-17. Print.
3. HSG Pharos Investigators. “At Risk for Huntington Disease: The PHAROS (Prospective Huntington At Risk Observational Study) Cohort Enrolled.” JAMA Neurology63.7 (2006): 991-96. Print.
4. Tabrizi Et Al. “Potential Endpoints for Clinical Trials in Premanifest and Early Huntington’s Disease in the TRACK-HD Study: Analysis of 24 Month Observational Data.” The Lancet 11.1 (2012): 42-53. Print.
HOPES summary of the talks from scientists and clinicians
Note: This article includes references to Dimebon, which is no longer being considered as a potential treatment for HD after the HORIZON clinical trial showed that Dimebon was not better than a placebo. For more information, click here
Lisa Ellerby, PhD, Buck Institute for Age Research
Target Validation in Huntington’s Disease
Dr. Ellerby’s talk focused on the question: “What are possible biological targets for drugs designed to treat HD?” Therapeutic drugs work by targeting specific processes in the human body that have gone awry in disease. For example, the common symptom chorea in HD is thought to be a result of the increased activity of the neurotransmitter dopamine. Tetrabenazine is used to treat chorea because the drug reduces the amount of dopamine in the brain.
At present, the pharmaceutical industry is focused on developing therapeutics for approximately 200 to 300 different targets in the human body that may be related to HD. However, those few hundred targets represent a very small subset of all possible biological targets and it is possible that drugs that have been created for other diseases could have therapeutic benefits for individuals with HD. One example of this is Dimebon, a drug that was originally used as an anti-histamine and is now being studied in clinical trials for HD because of its neuroprotective effects.
Dr. Ellerby is interested in identifying targets that play specific roles in the death of neurons in HD. While it is well known that the mutated Huntingtin protein (Htt) results in the neurodegeneration characteristic of HD, Dr. Ellerby’s research is important because it can provide insight into how this neuronal death occurs. Her lab used small interfering RNA (siRNA) to block the production of different proteins and then assessed the effects of these knockdowns on neuronal death. If shutting off a particular target results in decreased neuronal death, it is possible that this target plays a role in neurodegeneration due to mutant Htt. These experiments found that blocking the activity of proteases, enzymes that break down other proteins, reduces the death of neurons in a cellular model of HD. Specifically, Dr. Ellerby mentioned that decreasing the level of a family of proteases known as matrix metalloproteases (MMP) reduces the toxicity of mutant Htt. By using siRNA to identify targets that play a role in HD, Dr. Ellerby’s research is laying a foundation for the discovery and development of drugs that can prevent, treat, and reverse the devastating effects of HD.
Jill Larimore, BSc, 4th year graduate student in neurobiology at UCSF
Immune System Dysfunction in Huntington’s Disease
Ms. Larimore, as a member of Dr. Muchowski’s lab, researches the effect of HD on immune system function. Using yeast and animal models, her lab explores the HD on the molecular level in order to find new therapeutic targets. Ms. Larimore began her talk by explaining the immune system of the brain and the role of microglia cells. These specialized cells differ from those found in the peripheral immune system (i.e. the immune system which operates in all parts of the body besides the brain and spinal cord). Although the blood-brain barrier normally keeps these immune systems apart, Larimore’s research interestingly showed that there was peripheral immune system activation in HD patients. This indicates that the neurological symptoms of HD are either paralleled in the peripheral immune system or communication between cells traverses the blood-brain barrier to connect the two immune systems.
The Muchowski lab’s research also showed that HD increased inflammatory response in both the neural and peripheral immune system, even before manifestations of HD symptoms. Inflammation is an acute immune response that counters tissue injury by releasing chemical signals in the area of injury. Physical inflammation acts as a barrier against the spread of infection while immune cells repair the damaged tissue. Although normally beneficial, inflammation can be harmful when it becomes chronic and remains after healing. In HD patients, a key immune protein, interleukin-6 (IL-6) was found at higher concentrations both in the brain and body. IL-6 helps activate and regulate inflammatory response in the immune system, and indicates immune activity when found in heightened concentrations. In the brain, microglia activation increased as well, indicating microglia were responding to tissue damage in the brain. While immune activation could potentially be a natural healing response, Muchowski’s lab hypothesized that it was chronic inflammation that contributes to HD progression.
Similar inflammatory symptoms found in other neurodegenerative diseases have been extensively researched. Treatments have been found to regulate the heightened inflammatory response that occurs when certain immune proteins are activated. In mouse models of Alzheimer’s disease, the cannabinoid type 2 receptor (CB2) in the brain was found to decrease IL-6 and other proteins involved in the immune response in both the peripheral and neural immune systems. Inhibition of the CB2 receptor in a mouse model of HD worsened symptoms, as shown in behavioral assays (testing the mouse for motor functions and balance). Activating the CB2 receptor resulted in improved coordination and motor function, and slowed the onset of HD symptoms. Because CB2 therapeutics are already in clinical trials for autoimmune diseases, if CB2 is found to be beneficial in HD models by decreasing inflammation in the brain and the peripheral immune system these drugs could potentially be clinically tested as a therapy for HD.
Jan Nolta, PhD, Stem Cell Program, UC Davis
Working toward mesenchymal stem cell-based therapies for HD
Dr. Jan Nolta, director of stem cell research at UC Davis, presented on recent developments in her work on therapies for HD using mesenchymal stem cells (MSCs). MSCs have been found to deliver protein products throughout tissue for 18 months at a time. MSCs can potentially be engineered to deliver proteins that help prevent neurodegeneration to the brain. MSCs themselves exhibit neuroprotective activities. They restore synaptic connections, decrease inflammation, decrease neuron death and increase vascularization. Using vessels in the brain as train tracks, they are able to travel throughout the brain to assist other cells. Videos taken under a microscope show that MSCs are “social cells,” meaning they are constantly communicating with other cells around them. By interacting with another cell, an MSC can sense the needs of that particular cell and initiate a flow of appropriate nutrients directly into the other cell. In this way, MSCs act as cellular “paramedics” of the body.
One possibility for an HD therapy involves injecting MSCs into the brain where the cells could help reduce neurodegeneration by saving damaged neurons. Scientists at UC Davis conducted tests on non-human primates to ensure that injecting MSCs into the brain is safe for humans. Safety testing was recently completed with MSCs being injected through the skull into the brains of fetal non-human primates. Fortunately, results showed that after 5 months, the MSCs were still present. This means MSCs will be able to stay in the brain for a good length of time, theoretically assisting neurons and preventing additional cell death. Also, no tumors or tissue abnormalities were detected, indicating that MSC injection is largely safe. More studies about the intracranial transplantation and long-term MSC safety are needed.
Research on MSCs in Dr. Nolta’s lab currently involves three main goals: test bone marrow-derived MSCs to see if they restore neurons in non-human primates, test MSCs for the ability to secrete factors like brain-derived neurotrophic factor (BDNF) that help brain cell function, and to investigate MSC production of siRNA. Dr. Nolta was happy to announce that the FDA recently approved injection of MSCs into the central nervous system of individuals with another disease called amyotrophic lateral sclerosis. This sets an important precedent that will increase the likelihood that Dr. Nolta’s eventual therapy will work in other diseases.
Michael Geschwind, MD PhD, UC San Francisco Memory and Aging Center
Update on Clinical Studies and Trials in Huntington’s Disease
Dr. Michael Geschwind, a neurologist at the UCSF Memory and Aging Center, provided updates about clinical trials in HD. First, he reviewed the two types of clinical research: observational and clinical trials. An observational study is a type of study in which individuals are observed and certain outcomes are measured (such as motor control or mental function) but no attempt is made to affect the outcome in the form of treatment or therapy. In contrast, a randomized double-blind clinical trial is a study in which each individual is assigned randomly to a treatment group (experimental therapy) or a control group (placebo or standard therapy) and the outcomes are compared. Currently, there is important and promising HD-related clinical research being conducted both within and outside of the United States. The following paragraphs summarize the significant points regarding recent or ongoing studies in the HD field.
The PREDICT-HD study is an observational study that began in 2001, was expanded in 2008, and is still underway. The ultimate goal of the PREDICT-HD study is to define the earliest biological and clinical features of HD before at-risk individuals have diagnosable symptoms of the disease. While the current approach is to treat HD at the beginning of the onset of symptoms, this study aims to help design future studies of experimental drugs aimed at slowing or postponing the onset of HD in the at-risk population prior to observable symptoms. The PREDICT-HD study has identified markers that were shown to appear long before an individual would expect to be diagnosed. One marker is CAG repeat length: CAG stands for the nucleotides (DNA building blocks), cytosine, adenine, and guanine. The HD mutation consists of multiple repeats of CAG in the DNA. This study validated the CAG repeat length-age formula, in which the CAG repeat length for an individual could estimate the average age of HD onset. In general, fewer than 30 repeats is considered normal, whereas more than 39 repeats means the person will likely develop HD in a normal lifespan. To read more about CAG repeat lengths click here. Other markers such as the size of ventricles in the brain and the volume of other specific brain areas (i.e. striatum) were also found. In short, the PREDICT study has validated models for predicting motor onset of HD, which will ultimately increase the likelihood of treating HD before patients become symptomatic.
The DIMOND-HD study was a phase II clinical trial investigating the efficacy of the drug Dimebon, which is a small molecule that inhibits nerve cell death. This drug has been shown to decrease cognitive impairment in Alzheimer’s patients, and has been shown to improve cognition and memory in rats. Dimebon is often referred to as latrepirdine. The DIMOND-HD study evaluated the safety of administering Dimebon for 3 months and the efficacy of Dimebon in improving cognitive, motor, and overall function in subjects with Huntington’s Disease. The study was completed in the summer of 2008, and showed that Dimebon is a well-tolerated drug that generally improves cognition in HD. The researchers concluded that the drug should be tested in phase III clinical trials, which has resulted in the HORIZON trial described below. To read more about Dimebon click here.
The HORIZON study is a randomized, double-blind, placebo-controlled study that is ongoing at 37 sites, spanning 7 countries. The study is in phase III of clinical trials, and also aims to expand upon the results of the DIMOND-HD study and determine if Dimebon (latrepiridine) safely improves cognition in patients with Huntington’s disease.
The HART study is also a randomized, double-blind, placebo controlled study that is ongoing in both Europe and North America. The purpose of the study is to determine if ACR-16, also known as pridopidine and Huntexil, is effective and safe in the symptomatic treatment of HD. ACR-16 is a dopamine stabilizer, which means that it works to help regulate the many functions of dopamine in the striatum and other areas of the brain. ACR-16 has passed phase II of the clinical trials in Europe, and has been allowed to be tested in stage III in North America (US and Canada). Initial results of the clinical trials are promising, and have shown that ACR-16 can improve motor control and may translate to 0.5-1.5 years of disease improvement in voluntary and involuntary movements. To read more about ACR-16, click
The following table outlines the types of characteristics researchers are looking for in each of the ongoing HD Clinical Trials described above. For more information, click on the links provided.
Inclusion Criteria for HD Clinical Trials
|PREDICT-HD StudyFor more information on the PREDICT-HD study click here||• Gene negative and gene positive individuals: specifically, men and women at risk for HD, who have been tested for the HD gene mutation, and who have not been diagnosed with symptoms of HD (CAG > or equal to 36 for CAG-expanded group or CAG < 36 for CAG-norm group).
• 18 years of age or older
• Able to commit to a minimum of 5 yearly evaluations
• Commitment of a companion to attend visits or complete surveys via mail
• Able to undergo a MRI
|HORIZON StudyFor more information on the HORIZON study click here||• Have clinical features of HD and a CAG polyglutamine repeat expansion ≥ 36• Have cognitive impairment as noted by the following:
1. A screening MMSE and a baseline (pre-dose) MMSE score between 10 and 26 (inclusive); and
2. A subjective assessment of cognitive impairment with decline from pre-HD levels by the Investigator after interviewing the subject and caregiver;
• Are willing and able to give informed consent
• Aged 30 years or older
• Have a caregiver who assists/spends time with the subject at least five days per week for at least three hours per day and has intimate knowledge of the subject’s cognitive, functional, and emotional states, and of the subject’s personal care.
|HART StudyFor more information on the HART study click here||• Able to provide written Informed Consent prior to any study related procedure, including consent to genotyping of the CYP2D6 gene.• Clinical features of HD, and a positive family history and/or the presence of ≥ 36 CAG repeats in the Huntington gene.
• Male or female age ≥ 30 years.
• Willing and able to take oral medication and to comply with the study specific procedures.
• Ambulatory, being able to travel to the assessment center, and judged by the Investigator as likely to be able to continue to travel for the duration of the study.
• Availability of a caregiver or family member to accompany the subject to two visits.
• A sum of ≥ 10 points on the mMS at the screening visit.
• For subjects taking allowed antidepressants or other psychotropic medication, the dosing of medication must have been kept constant for at least 6 weeks before enrollment.
F. Clum, C. Garnett, T. Wang and A, Lanctot, 2010More
Drug Summary: Pridopidine, also known as Huntexil or ACR-16, is a dopamine stabilizer intended to improve voluntary movements and reduce chorea. Initial clinical trials – the MermaiHD and HART studies – show promising results, but drug regulation agencies have requested another trial before pridopidine can be sold to the general public.
Dopamine in the HD Brain
The brain plays a delicate balancing act: it needs to maintain the right levels of many brain chemicals in order to orchestrate movements and execute thoughts. In people with Huntington’s disease (HD), that balance is threatened; the brain has trouble regulating neurotransmitters, chemicals in the brain that transfer messages between neurons. This causes miscommunication between different parts of the brain. As a result, people with HD have less control over behaviors and movements that are usually directed by the affected neurotransmitters, as described in greater detail here. Pridopidine, which is being investigated as a treatment for the motor symptoms of HD, is thought to restore the balance of neurotransmitters that the brain needs to function.
Specifically, pridopidine is believed to work by stabilizing levels of the neurotransmitter dopamine in the brain. Dopamine has a number of different roles depending on what part of the brain it acts on, but in the HD brain, the most relevant function is its effects on motion. Dopamine in the striatum, a part of the brain responsible for planning and controlling movements, helps coordinate voluntary motions (like walking or waving) and prevent involuntary motions (like the unwanted dance-like movements of chorea), as discussed in more detail here.
However, sometimes there’s too much of a good thing. When there’s too much dopamine in certain parts of the striatum, the brain has trouble stopping involuntary movements, which causes chorea. On the other hand, when there’s too little, the brain can’t start voluntary movements, and the symptoms – such as stiffness, staggering, and difficulties speaking – get in the way of everyday life. The brain walks a tightrope as it tries to maintain the right balance of neurotransmitters, and the slightest disturbance can cause movements to falter (Andre et al., 2011).
How Pridopidine Works
As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there’s too much, and increase its effects when there’s too little. When dopamine levels are too high, pridopidine interacts with dopamine receptors, which act as the “ears” the neuron uses to “hear” dopamine. These receptors have a very specific shape that allows them to bind and recognize dopamine, and when levels of dopamine are high, the receptors change shape as they become more active. Pridopidine is particularly attracted to the “active” form of the receptor and lodges itself in the spot where dopamine usually binds, preventing dopamine from interacting with the receptor. In this way, pridopidine blocks the dopamine receptor from sensing and responding to dopamine when dopamine levels are too high (Pontel et al., 2010).
Conversely, when levels of dopamine are low, pridopidine has a round-about way of increasing dopamine production. HD affects more than just dopamine: low levels of the neurotransmitter glutamate in a region of the brain called the cortex are also associated with the disease (Pontel et al., 2010). The cortex is the part of our brain that helps us think and plan, and tells the striatum what voluntary movements to perform. Pridopidine raises glutamate levels in the cortex, allowing it to communicate better with the striatum. This increases dopamine levels in the parts of the striatum that had too little. By increasing glutamate signaling in the cortex, pridopidine increases dopamine levels in certain parts of the striatum, allowing voluntary movements to occur (Andre et al., 2011).
Pridopidine therefore plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion.
Research on HD
Neurosearch, a pharmaceutical company based in Sweden, has conducted two different clinical trials on pridopidine.
The MermaiHD study was a phase III clinical trial, conducted in 32 centers spread across eight countries in Europe. 437 HD patients were randomly assigned to one of three groups: one treatment group received 45 mg of pridopidine once per day; the second treatment group received 45 mg of pridopidine twice per day; the control group received a placebo. To prevent potential bias, MermaiHD was a double-blind study; neither doctors nor patients knew whether the patient was receiving pridopidine.
After 6 months, patients were given the opportunity to continue participating in the study for another 6 months. In this “open-label” phase, the 357 patients who opted to proceed took 45 mg of pridopidine twice daily – no patients were given placebo. The purpose of the open-label segment of the study was to test whether pridopidine is safe and effective for longer periods of time.
Preliminary results suggest that pridopidine might help HD patients control motor symptoms. Doctors measured patients’ progress using the modified Motor Score (mMS), which tests a patient’s ability to perform voluntary movements. Results suggest that patients taking pridopidine performed better on the mMS; patients taking 45 mg of pridopidine twice daily averaged a 1.0 point improvement on the test. However, the results of the mMS did not reach the goals that the scientists had set out to prove: these results reached a statistical significance level of p=0.042. This means that there is a 4.2% probability that pridopidine is no better than a placebo, and that these results occurred by chance; they had originally aimed for a p=0.025.
However, further data analysis indicates that pridopidine may still hold promise. The mMS is just a subsection of a more widely-used test called the Unified Huntington’s Disease Rating Scale (UHDRS), which is described in more detail here. When measured on the motor category of the UHDRS, a test called the UHDRS-TMS, the results were very significant: Patients taking 45 mg of pridopidine twice per day had a 3.0 point improvement, at a statistical significance level of p=0.004. To put that in perspective, HD patients generally experience a 3-point annual decline in their UHDRS-TMS score. This strongly indicates that pridopidine improves motor symptoms of HD.
Furthermore, pridopidine did not appear to have notable side effects, and didn’t make other symptoms of the disease worse. This was a concern because other treatments, such as tetrabenazine, sometimes cause depression and other side effects if they change neurotransmitters too much in the wrong parts of the brain, as described here.
In the HART study, Neurosearch and the Huntington Study Group teamed up to study pridopidine further. The HART study was a phase IIb clinical trial, which measures how well a drug works at the prescribed dose. The study was also conducted to see whether pridopidine is effective and safe, and to establish an optimal dose. HART enrolled 227 patients, and was run in 28 centers across America and Canada. Like the MermaiHD study, the HART study was randomized, double-blind, and placebo-controlled.
To determine the dose, there was one placebo group and three treatment groups; patients received 10 mg, 22.5 mg, or 45 mg of pridopidine twice per day.
After just 12 weeks, a significant effect was seen in the group taking the largest dose, 45 mg. Total motor function, as measured by the UHDRS-TMS, improved by 2.8 points, which was statistically significant with a p=0.039. Again, the original test – the mMS – did not show statistical significance, though it did show a strong trend with p=0.078.
The HART study backed up the findings of the MermaiHD study and also helped scientists determine which dose of pridopidine is most effective. This study will continue in an open-label phase, where patients who participated in HART are given the opportunity to continue taking pridopidine until the U.S. Food and Drug Administration (FDA) decides whether or not to approve pridopidine.
Pridopidine significantly improves motor function, and has a positive effect on both voluntary and involuntary motor actions. Furthermore, it is very well tolerated, even when patients are taking other drugs, such as antipsychotics. However, pridopidine isn’t a “miracle drug” – while the findings are very hopeful, the drug has only been shown to improve motor symptoms; there is no evidence that it can “cure” the disease. Also, pridopidine’s effects seem to be limited to motor symptoms; patients experienced no significant changes in cognition, mood, or general ability to function in day-to-day life.
Individually, neither MermaiHD nor HART lived up to the original standards the researchers had set out to meet. However, statistical significance was reached when the results of the two studies were combined, and when the UHDRS-TMS was used to evaluate patients. Based on these results, Neurosearch lobbied the FDA, which regulates American drugs, and the European Medicines Agency (EMA), which regulates European drugs, to accept pridopidine as a treatment for HD. However, both organizations have asked for another phase III clinical trial to validate that pridopidine lives up to these promises. Neurosearch has declared that it will carry out a further trial, but has not yet announced further details. If it successfully passes this trial, the FDA and EMA would be likely to allow pridopidine to start being marketed as a treatment for HD.
- André VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington’s disease: A balancing act. CNS Neurosci Ther. 2010 Jun;16(3):163-78. Epub 2010 Apr 8. Review. This article discusses dopamine and glutamate signaling in the brain, and is very technical.
- Miller, Marsha L. “The American ACR16 Trial Results.” HDAC.org. Huntington’s Disease Advocacy Center, 14 Oct. 2010. Web. 5 July 2011. This article discusses the MermaiHD and HART studies, and is moderately difficult.
- Ponten H, Kullingsjö J, Lagerkvist S, Martin P, Pettersson F, Sonesson C, Waters S, Waters N. In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol. 2010 Oct 10;644(1-3):88-95. Epub 2010 Jul 24. This highly technical article discusses how Pridopidine is believed to work in the brain.
M. Hedlin, 7.16.11More
The brand name under which Lundbeck markets the drug Tetrabenazine in the U.S.More
Vesicular monoamine transporters (VMATs) are proteins in neurons that help put neurotransmitters into vesicles so they can be released into the synapse. VMATs can be inhibited by the drugs tetrabenazine and deutetrabenazine.More
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
Huntington’s disease (HD), an inherited neurodegenerative disorder, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. HD is often characterized by the motor symptoms that it causes.
Huntington’s disease (HD), an inherited neurodegenerative disorder, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. HD is often characterized by the motor symptoms that it causes. In fact, when HD was first discovered it was called Huntington’s chorea, as a reference to the uncontrollable, dance-like movement that is common among people with HD. Motor symptoms, though not always the first symptoms to appear, are often the reason that people with HD first see a doctor. Before genetic testing for the expanded CAG repeat within the Huntington gene became available, doctors could only make diagnoses according to motor symptoms. Even today, these symptoms are an important part of the criteria for clinical diagnosis; they generally define the age of onset of HD in an individual.
What are the motor symptoms that occur with HD?
The progression of HD is different in every individual, but the following list contains most of the physical conditions that occur frequently in adult-onset HD. Keep in mind that not everyone with HD will experience all symptoms, and the progression from stage to stage is only a generalization. The time it takes to move from one stage to the next is also highly variable. It is important to note as well that juvenile HD exhibits motor symptoms that can be quite different from the adult form. (For more information on juvenile HD, click here).
- Changes in coordination
- Some involuntary movement (such as irregular, sudden jerks of limbs)
- Restlessness, desire to move about
- Twitching, muscle spasms, tics
- Less control over handwriting
- Facial grimaces
- Difficulty with coordinated activities, such as driving
- Some rigidity
- Dystonia (prolonged muscle contractions), often of the face, neck, and back
- More involuntary movements
- Trouble with balance and walking
- Chorea, twisting and writhing motions, jerks
- Staggering, swaying, disjointed gait (can seem like intoxication)
- Speech difficulties, including poor articulation, grunting, and abnormal speech patterns
- Problems swallowing
- Trouble with activities that require manual dexterity
- Slow voluntary movements, difficulty initiating movement
- Inability to control speed and force of movement
- Slow reaction time
- General weakness
- Bradykinesia (difficulty initiating and continuing movements)
- Severe chorea (less common)
- Serious weight loss
- Inability to walk
- Inability to speak
- Swallowing problems, which create danger of choking
- Inability to care for oneself
Though HD is not fatal in and of itself, the conditions that it causes can eventually lead to death. One of the most serious concerns for people with late stage HD is loss of control of the throat muscles. This condition makes swallowing difficult, and ultimately, dangerous. Everyone’s body is constructed with two tubes that begin below the throat; one, the esophagus, leads to the stomach, and the other, the trachea, leads to the lungs. Usually, we have no trouble making sure that food passes through our esophagus and not into our trachea. We do this without thinking, and rarely does something go “down the wrong pipe.” For people with late stage HD, however, this process of sorting food and air often functions poorly. As a result, food can get caught in the trachea and lead to choking. If food gets caught in the lungs, it can lead to an infection known as aspiration pneumonia. Although most people recover from pneumonia, people with HD usually have compromised immune systems, and therefore are unlikely to recover from such a severe infection. (For more information on other potential complications of HD, click here.
What exactly is chorea?
Chorea is a disorder of the nervous system that occurs in multiple clinical conditions. In other words, it is not limited to HD, even though it is one of the classic symptoms associated with this particular disease. Chorea is characterized by spontaneous, uncontrollable, irregular movements, generally of the limbs and face. It can appear as unexpected jerks or twisting, writhing motions. These unpredictable movements contribute to poor balance, and the resulting walking difficulties lead to the staggering, swaying gait associated with HD. It is this irregular walking pattern that can make people with HD appear intoxicated, and also explains the root of the word chorea, which is the Greek word for dance. In the extreme, chorea can be a constant stream of violent movement. Severe choreic motions are known as ballismus.
Chorea occurs in 90% of people with HD, and increases over the first 10 years following onset. Although the specific motions of chorea can vary from one individual to the next, there are often consistent patterns within individuals. Chorea is usually present during waking hours, and cannot generally be suppressed. As HD progresses, chorea normally gives way to other movement difficulties, such as rigidity and bradykinesia.
How can motor symptoms be treated?
Unfortunately, as there is no cure for HD, there is also no cure for the motor symptoms that accompany the disease. There are, however, drugs and supplements available that may lessen certain motor symptoms of HD. It is also possible to treat many of the behavioral symptoms, which can greatly improve quality of life. (For more information on drugs and supplements that are used to treat HD, click here, and for information about behavioral symptoms, click here). Under certain circumstances, there is a surgical procedure that can be performed, which involves making stereotactic lesions in a part of the brain called the thalamus. This procedure may alleviate motor symptoms, but it can only be performed when no cognitive decline is evident, and ultimately it does not halt the progression of the disease.
In addition to clinical treatments, there are other means of dealing with motor difficulties. One place to start is with health professionals: speech pathologists, physical therapists, and occupational therapists. Speech pathologists help with the mechanics of eating and drinking, as well as the loudness and articulation of speech. They can provide strategies for improving communication within the family and can also begin discussions about the use of a feeding tube, in the event that such a step becomes necessary. Exercise can be a very positive means of therapy, with physical, psychological, and emotional benefits. Physical therapists develop specialized exercise programs, usually to improve stretching and range of motion. They also advise people with HD about the use of walkers and wheelchairs. (For more information on exercise and HD, click here). Occupational therapists find ways to help people compensate for their inability to perform daily tasks, like eating and dressing. Often this involves adjusting the surrounding environment to better suit the needs of the individual with HD. Even small changes can make him or her feel more comfortable and capable, and thereby make his or her symptoms less problematic in daily life. (For suggestions on environmental adjustments, click here).
Motor symptoms can also be managed through lifestyle adjustments. Exercise, as previously mentioned, diet, and stress all affect overall health, and may contribute to the severity of symptoms. You should always consult your doctor before making any changes to your normal routine, but by clicking here, you can learn more about lifestyle adjustments that could potentially have positive effects.
What causes motor symptoms?
The reasons why HD causes motor symptoms are very complex and not entirely clear. However, researchers have learned a great deal about what may be at the root of the problem. In order to begin discussing why motor symptoms occur, we first have to look at how movement is organized in the brain. Motor control operates through two main pathways, which link the cortex (the outer part of the brain, responsible for sophisticated functions) with the basal ganglia (a grouping of cells found deep within the brain, responsible for more basic functions). These pathways are termed “direct” and “indirect.” Before continuing, you may want to take a moment to review these two pathways described here, in the Neurobiology of HD section.
After reviewing the basics of the direct and indirect motor pathways, we can examine this schematic diagram that combines the two (Figure 1). Notice that there is an additional pathway: nerve cells in the striatum also project, or link, onto a region of the basal ganglia called the substantia nigra (as well as the globus pallidus), which then projects directly back onto the striatum. Though it may seem odd to have a simple loop added to this system, we will see that this pathway, the striatonigral pathway, is very important to motor function.
In looking at the diagram, notice that along each projection arrow there is the name of a particular chemical, known as a neurotransmitter. Neurotransmitters are the means by which cells (and brain regions) communicate with each other. One cell, the presynaptic cell, releases a neurotransmitter and another cell, the postsynaptic cell, absorbs it. This chemical signal causes the postsynaptic cell to take some sort of action, such as releasing a neurotransmitter or actively not releasing one. Its response will then influence other cells farther down the line. This progression of cell-to-cell chemical communication is the nuts and bolts of the motor control pathways that we have been discussing.
You can see from the diagram that each motor pathway involves a complex combination of neurotransmitters. Let’s walk through the various pathways to get a clearer picture of how this all works. Remember though, it is the overall concept of the pathways that is important, not the names of each brain region and neurotransmitter.
The first step for all motor pathways is the cortex receiving sensory information from the outside world, via sight, touch, hearing, etc. It transmits this information to the striatum (part of the basal ganglia) in chemical form, using a common neurotransmitter called glutamate. Glutamate then causes the cells of the striatum to take action in the following ways:
The direct pathway: Nerve cells in the striatum project onto the internal part of the globus pallidus, using the neurotransmitters GABA and substance P. The cells of the globus pallidus then use GABA in their projections to the thalamus, a major relay and control center of the brain. The thalamus completes the loop back to the cortex using more neurotransmitters, sending its signals directly to the part of the cortex devoted to motor control, the motor cortex. The motor cortex responds to these signals (which originated in the basal ganglia, remember) by physically moving the body in the appropriate way.
The indirect pathway: Striatal cells (cells in the striatum) use GABA and enkephalin to project onto the outer part of the globus pallidus. Globus pallidus cells then project to the subthalamus using GABA, which in turn projects to the internal globus pallidus using glutamate. From there the pathway is the same as the direct pathway, progressing to the thalamus and then the motor cortex.
An important note: Certain neurotransmitters are termed “excitatory” and others “inhibitory.” Excitatory neurotransmitters cause an action to take place in another cell or part of the body. Inhibitory neurotransmitters prevent an action from occurring. All projections that come from the basal ganglia (including the striatum, globus pallidus, and substantia nigra) are inhibitory. We know that these cells are involved in controlling the movement of the body, so therefore the neurotransmitters from cells in the basal ganglia serve to prevent (or inhibit) movement. Imagine you are sitting at a desk, writing on a piece of paper. You are moving your hand and arm, but the rest of your body is still. In order to keep the rest of your body still, the cells in your basal ganglia are releasing inhibitory neurotransmitters constantly. In this state, cells are said to be operating at their baseline firing rate. “Baseline” refers to what is normal, because most of the time we want to prevent movement in at least some parts of our body, and “firing rate” refers to how frequently the neurotransmitters are released. Consider that while you are at the desk writing, you see that you have made a mistake. This visual sensory information reaches your cortex, and then is sent to your basal ganglia. The basal ganglia realize that you will need to tell your other arm to reach for an eraser. In order to stop inhibiting movement in that arm, the basal ganglia must adjust its release of inhibitory neurotransmitters. This modified signal is passed to the thalamus and then the motor cortex. Because the motor cortex is no longer inhibited as much, it can tell your other arm to reach for the eraser. When you have finished using that arm, neurotransmitter release returns to normal, to the baseline firing rate.
How does all this work in HD? Mutant huntingtin protein is expressed in all the cells of the body, but the most and earliest damage is seen in the basal ganglia, and the striatum in particular. The precise mechanism by which mutant huntingtin harms cells and causes them to behave differently is not clear. However, we know that mutant huntingtin causes serious problems with cell function and eventually leads to cell death. Here is where an understanding of motor pathways comes in handy. The early motor symptoms seen in HD are the result of damage to the striatum that impacts the indirect pathway (although both pathways are affected at the same time in juvenile HD). Damage from HD causes the striatum to release a weaker chemical signal, resulting in less inhibitory neurotransmitters, less inhibition of the motor cortex, and more movement. This movement is unintended, the result of a pathway error, and is therefore called “involuntary.” Involuntary movements include the fidgeting, tics, and chorea associated with early to middle stage HD. Later on in the disease the direct pathway becomes increasingly affected. In this case, the striatum still releases less inhibitory neurotransmitters, but in the direct pathway this action leads to more inhibition of the motor cortex and less movement. The result is rigidity of the body and bradykinesia, common to late stage HD. So, looking at how the direct and indirect motor pathways work and the motor symptoms we know to occur in HD, we can follow a logical route from damage in the striatum to actual symptoms. But what causes the neurotransmitter signals from the striatum to decrease in the first place? Let’s first take a look at the third motor pathway in the diagram.
The striatonigral pathway: Nerve cells in the striatum also project onto the substantia nigra, using GABA. The substantia nigra then responds with dopamine, projecting straight back onto the striatum. This dopamine signal influences both the direct and indirect pathways, but with different results, even though both pathways are responding to the same chemical signal. This is accomplished by having two different kinds of dopamine receptors on the post-synaptic cells in the striatum: D1 receptors link to the direct pathway and D2 receptors link to the indirect. Dopamine that goes to D1 receptors causes the striatum to release less inhibitory neurotransmitters, which ripples through the whole direct pathway and ultimately leads to inhibition of the motor cortex (preventing movement). Dopamine that goes to D2 receptors also causes the striatum to release less inhibitory neurotransmitters, but because of a different pathway progression, ultimately leads to less inhibition of the motor cortex (causing movement).
Researchers think that the answer to why HD causes the striatum to release a weaker chemical signal may be the striatonigral pathway and dopamine. As we have discussed, HD seems to over-stimulate the motor cortex via the indirect pathway and under-stimulate the motor cortex via the direct pathway. Interestingly, this pattern matches up with the influence of the striatonigral pathway on the other two pathways. When dopamine is released from the substantia nigra, it inhibits the striatum, causing it to release less inhibitory neurotransmitters. Let’s put these ideas together: if an excess of dopamine is released from the substantia nigra, the indirect pathway would over-stimulate the motor cortex and the direct pathway would under-stimulate it, just like in HD. You can see why researchers started to think that the striatonigral pathway and dopamine might be the key.
So what causes the substantia nigra to release more dopamine? For a potential answer we must trace the pathway back even further. Remember that as soon as the striatum receives a sensory message from the cortex, it sends a signal to the substantia nigra, via the neurotransmitter GABA, which then influences the substantia nigra’s release of dopamine. These two neurotransmitters go back and forth like a seesaw: more GABA means less dopamine and vice versa. Researchers have found that cells in the striatum that release GABA selectively degenerate due to damage from mutant huntingtin. GABA is an inhibitory neurotransmitter like all those in the basal ganglia. Therefore, if striatal cells are damaged and release less GABA, the substantia nigra is less inhibited and will release more dopamine. An increase in dopamine would inhibit the striatum, which is consistent with the pattern seen in HD.
It is important to note, however, that scientific studies have not been able to show conclusively that dopamine levels are increased in HD. Indeed, post-mortem studies of people with HD have shown elevated, depleted, and unchanged levels of dopamine in the brain. Additionally, the striatum uses GABA in its projections to both parts of the globus pallidus, not just the substantia nigra. Therefore, damage to the striatum from HD could lessen the release of GABA to the globus pallidus and thus the two main pathways directly, not just via the striatonigral pathway.
Nonetheless, many researchers are confident that dopamine is important to HD, even at endogenous, or natural, levels. Dopamine may in fact play an even more integral role in striatal cell damage, by causing the damage, not just influencing the pathway. One major question for researchers has been, why the striatum? Why is the basal ganglia harmed by mutant huntingtin, and not other cells? Recent studies suggest that the presence of dopamine is correlated with cell damage in HD. If this is the case, only cells in which dopamine was present would degenerate, and those with more dopamine would degenerate first. This theory would explain why cells in the striatum degenerate first. Charvin and others (2005) have shown that both dopamine and mutant huntingtin can activate a transcription factor known as c-jun. Transcription factors can influence a cell in many different ways; c-jun leads to programmed cell death, or apoptosis. When dopamine and mutant huntingtin are present together, the level of c-jun is greatly increased. The way that dopamine activates c-jun is as follows: dopamine can autooxidize, or in other words, spontaneously undergo a reaction that leads to reactive oxygen species (ROS). ROS are bad for the cell, and usually lead to cell damage. To prevent this damaged cell from hurting the rest of the body, the cell activates c-jun to start the process of programmed cell death (apoptosis). Therefore, the apoptosis of one cell is a good defense mechanism for the body. When mutant huntingtin is present, however, far too many cells induce apoptosis. Also, as we age, autooxidation of dopamine naturally increases. You can imagine that in someone with HD, more and more apoptosis due to dopamine combined with the presence of mutant huntingtin, could result in significant problems. This theory may therefore explain HD’s late age of onset. (For more information about the theory of oxidative stress and HD, click here).
Charvin and others proposed another role for dopamine in striatal cell damage. As previously mentioned, there are two kinds of dopamine receptors in the striatum: D1 for the direct pathway and D2 for the indirect. D2 receptors are more significantly implicated in HD. This makes sense, given that the indirect pathway is affected first. Charvin et al. suggest that D2 receptors are over-stimulated. Their theory also says that, as dopamine passes through the D2 receptors, it contributes to the formation of aggregates (or clumps) of the mutant huntingtin protein within the cell. Aggregates of mutant huntingtin are a common pathological marker in HD, meaning that they are present in cells affected by HD. It is unclear, however, what the function of these aggregates actually is. They may be harmful, helpful, or not have any effect on the cell at all. (For more information on protein aggregates, click here).
Scientific studies have consistently noted that dopamine receptors (D1 and D2) are depleted in HD. This may seem strange, as we have been suggesting that the presence of dopamine (or perhaps the excess of dopamine) is the reason why HD motor symptoms occur. Although the depletion of receptors is well known, the cause of the depletion is not. D2 receptors, for the indirect pathway, are depleted first, with more D1 receptors, for the direct pathway, disappearing as HD progresses. One possibility is that too much dopamine may be toxic to the receptors, thus killing them off. It may also be the case that cells try to protect themselves from an excess of dopamine, or its toxic influence in the presence of mutant huntingtin, by actively losing receptors. Another possibility is related to brain-derived neurotrophic factor (BDNF). BDNF is a chemical that protects cells in the brain, and its function has been shown to be impaired in HD. The loss of BDNF could make it much easier for receptors to be damaged, as well as allowing for the mutant huntingtin/dopamine synergistic damage to occur in the first place. (For more information on BDNF, click here). It is also possible that mutant huntingtin harms receptors directly. Regardless of the specific cause of receptor depletion, much damage from dopamine can occur by the time depletion becomes significant. Additionally, if the striatum is absorbing less dopamine, an increased release of dopamine could be triggered in the substantia nigra. A reduced number of receptors can also lead to greater sensitivity of the remaining receptors, ultimately resulting in more dopamine absorption and damage. As you can see, cell-to-cell communication is very complex and intricate. Though this fact makes it difficult to determine just how HD affects the brain, it does give researchers many ideas about what to look at next, as well as offer many possibilities for treatments.
So what does all this mean for HD treatments? Currently in the U.S. there are few medications that are prescribed to treat motor symptoms of HD, and none that are particularly aimed at chorea. However, experimental drugs that deplete dopamine have been reported to have positive effects on motor symptoms. The best-studied drug, tetrabenazine, should soon be available in the U.S. and will be discussed in detail in the chapter linked to below. As we learn more and more about the cause of HD damage in the brain, we can develop new treatments that are aimed at specific mechanisms. Future medications may target ROS production, dopamine absorption through D2 receptors, or initiation of the c-jun pathway, to name a few. These new kinds of treatments will hopefully prove to be more effective than current options, impacting the progression of HD in a meaningful way.
For further reading
- Bates, G., Harper, P., & Jones, L. Huntington’s Disease. New York: Oxford University Press, 2002. pp. 28-37, 276-281.
This book is a thorough review of current knowledge about HD, but is very scientifically-oriented.
- Canals, J.M., et al. “Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease.” 2004.Journal of Neuroscience. 24(35): 7727-7739.
An article about BDNF and HD.
- Charvin, D. “Unraveling a role for dopamine in Huntington’s disease: the dual role of reactive oxygen species and and D2 receptor stimulation.” 2005. PNAS? 102(34): 12218-12223.
This article presents the possible mechanisms for how dopamine may damage striatal cells.
- Dr. Joseph F. Smith Medical Library. “Huntington’s disease.” http://www.chclibrary .org/micromed/00051720.html
A description of motor symptoms and alternative treatments for HD, such as occupational, speech, and physical therapies.
- Emedicine.com. “Huntington disease dementia.” http://www.emedicine.com/me d/topic3111.htm
Brief review of motor symptoms associated with HD.
- Gazzaniga, M.S., Irvy, R.B., & Mangun, G.R. Cognitive Neuroscience: The Biology of the Mind. New York: W.W. Norton & Company, 2002. pp. 488-492.
This is a textbook covering many topics in neurobiology. It is rather technical.
- HDNY at Columbia University. “Speech pathology”: http://www.hdny.org/speech.html, “Social implications of motor disorders”: http://www.hdny.org/problems.htm, “Environmental adjustments”: http://www.hdny.org/rehab.html
The HDNY website is very helpful as a general resource, even outside the NY area. These pages are particularly relevant to motor symptoms.
- Health-cares.net. “What is Huntington’s chorea?”: http://neurol ogy.health-cares.net/huntingtons-chorea.php, “What causes chorea?”: http://neurology.he alth-cares.net/chorea-causes.php
This website discusses HD and other forms of chorea.
- Hickey, M.A., et al. “The role of dopamine in motor systems in the R6/2 transgenic mouse model of Huntington’s disease.” 2002. Journal of Neurochemistry. 81: 46-59.
A good study of dopamine and HD in a mouse model.
- International Huntington Association. “Huntington’s disease.” http://www.huntington-assoc .com/huntin.htm
A summary of the progression of HD, in terms of motor, cognitive, and behavioral symptoms.
- Jakel, R.J., & Maragos, W.F. “Neuronal cell death in Huntington’s disease: a potential role for dopamine.” 2000. Trends in Neuroscience, 23: 239-245.
This is a good article that reviews the potential mechanisms for cell damage as a result of HD.
- Nieuwenhuys, R., Voogd, J., & van Huijzen, C. The Human Central Nervous System: a Synopsis and Atlas. New York: Springer-Verlag, 1981. pp. 169-173.
A highly technical book that details neuroanatomy.
- Petersen, A., et al. “Mice transgenic for exon1 of the Huntington’s disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine.” 2001. European Journal of Neuroscience. 14:1425-1435.
This is a rather complex article that discusses the potential for dopamine toxicity in striatal cells.
- Pineda, J.R., et al. “Brain-derived neurotrophic factor modulates dopaminergic deficits in a mouse model of Huntington’s disease.” 2005. Journal of Neurochemistry. 93: 1057-1068.
More on BDNF.
- Reynolds, D., et al. “Dopamine modulates the susceptibility of striatal neurons to 3-nitropropionic acid in the rat model of Huntington’s disease.” 1998. Journal of Neuroscience. 18(23): 10116-10127.
This article is one of the earlier articles to show that dopamine is important to cell damage in HD.
- UCLA Medical Center. “How is Huntington’s disease treated?” http://neurosurgery.ucla.edu/Diagnoses/Movement/MovementDis_2.html
A brief overview of medical and surgical treatment options, from the neurosurgery department at UCLA.
- We Move. “Medical management of Huntington’s disease.” http://www.wemove.org/hd/hd_tr e_mm.html
A brief discussion of available medical treatments for HD and their potential consequences.
C. Tobin 6-29-06More