All posts in Research Basics


Neuroimaging refers to techniques that produce images of the brain without requiring surgery, incision of the skin, or any direct contact with the inside of the body.  Because these technologies enable noninvasive visualization of the structure and functionality of the brain, neuroimaging has become a powerful tool for both research and medical diagnosis.  Although still relatively young, the field of neuroimaging has rapidly advanced over the years due to breakthroughs in technology and computational methods.  Applications of neuroimaging techniques have likewise become far-reaching.

This article will cover three of the most common techniques in neuroimaging: computerized tomography (CT), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET).  You will likely come across at least one of these techniques while reading about Huntington’s disease (HD) news and research.  For each technique, the article will discuss its working mechanism, its pros and cons, and its relevance to HD.

Computerized tomography (CT)^

Computerized tomography (CT) is a medical imaging procedure that uses x-rays to generate detailed pictures of structures inside the body.  It has become a valuable tool for medical diagnosis and for planning, guiding, and monitoring therapy.

Attribution: Aaron G. Filler, MD, PhDA CT scan of a human brain. (Source: Aaron G. Filler, MD, PhD)

How CT works^

A CT scan uses X-rays positioned at different angles to create cross-sectional images of the brain.  During a CT scan, a movable X-ray source is rotated around the patient’s head.  Detectors record information about the intensity of the rays transmitted through the head at each angle, which is sort of like taking a series of two-dimensional snapshots.  The computer then uses an algorithm to combine all the individual snapshots from different axes of rotation of the source together and to reconstruct them into a 3-D, cross-sectional image.  By allowing doctors and researchers to view the full volume of the head, CT scans can provide much more information about the brain than traditional X-ray scans, which only offer a two-dimensional representation of the brain.

Advantages and Disadvantages of CT^

CT scans are painless, fast, and cost-effective.  CT can image bone, blood vessels, and soft tissue simultaneously and provides very detailed images of many types of tissue.  There are, however, several risks associated with the use of CT.  The main risks, according to the US Food and Drug Administration, are:

  • An increased lifetime risk of cancer due to x-ray radiation exposure
  • Possible allergic reactions or kidney failure due to contrast agent, or “dye” that may be used in some cases to improve visualization
  • The need for additional follow-up tests after receiving abnormal test results or to monitor the effect of a treatment on disease

You and your physician should decide whether or not the benefits of getting the added information from a CT scan outweigh the possible risks.

CT and Huntington’s disease^

CT cannot by itself be used to diagnose HD, since other disorders or conditions can result in similar anatomical change in the brain; often it is used along with family history and medical records in order to provide a more detailed diagnosis.  (The same is true of MRI scans, which will be discussed in the upcoming section.) Doctors use CT (or MRI) to evaluate a patient with HD by checking for characteristic degeneration in the brain and ruling out other possible disorders.  A CT scan for a patient in the early stages of HD may appear normal, but a CT scan for a patient in advanced stages of the disease can often reveal significant degeneration – specifically, reduction in volume of certain regions of the basal ganglia.

Functional Magnetic Resonance Imaging (fMRI)^

Functional magnetic resonance imaging (fMRI) is a specialized form of MRI that indirectly provides information on brain activity by measuring changes in blood flow in the brain.

Public domain, NASA

An fMRI scan of a human brain. (Public domain)

How MRI works^

A traditional MRI scanner contains a very strong electromagnet, which generates a strong magnetic field inside the scanner.  When turned on, this causes randomly spinning protons, or positively charged particles, in the brain (in this case hydrogen protons from water molecules) to align themselves with the direction of the field.  (Think of how a compass needle at rest is aligned with the Earth’s magnetic field, which is why it always points north.) However, the protons still spin while in alignment in the field, and the axis of their spin isn’t perfectly parallel to the direction of the field – rather, the protons behave like wobbling tops. The rate at which the protons wobble is called resonance.

We can also think of resonance as the ability of a system to absorb energy delivered at a particular frequency.  To illustrate this concept, imagine that you are pushing a small child on a playground swing.  If you push the child too quickly or too slowly, the child won’t rise very high.  But if you give the child enough pushes at just the right frequency, the child will rise to the maximum height attainable due to the energy you have provided by pushing.  This frequency is called the resonant frequency of the swing, which is the rate at which the swing will naturally oscillate.  The swing absorbs the most energy when it is pushed at exactly this frequency.  Similarly, protons placed in a strong magnetic field will efficiently absorb energy when the energy is delivered at a particular resonant frequency, namely the rate of “wobbling.”  In the case of MRI, radio waves provide the “push” necessary to move the protons.

During a process called excitation, the MRI scanner emits energy in the form of radio waves at precisely the resonant frequency of protons.  These radio waves knock the protons out of alignment, causing them to flip and spin on their opposite ends.  In order to flip over, the protons have to absorb some energy from the radio waves.  When the radio signal is turned off, the protons flip back around to their original alignment, and in the process release the energy they have absorbed.  This released energy is called the MR (magnetic resonance) signal and can be measured by electromagnetic detectors around the subject.  A computer receives the MR signals as mathematical data and compiles them into an image.

Although fMRI uses the same principles as MRI, there is one important distinction.  MRI (often called structural MRI) reveals brain anatomy, while fMRI reveals brain function, often in the form of neural activity.  For this reason, fMRI is very useful for neuroscience and clinical research, while MRI is traditionally used for clinical characterization in the same manner as CT scans.

However, fMRI doesn’t reveal neural activity directly.  Recall that when neurons are active, they fire action potentials and send messages in the form of neurotransmitters to other neurons. (To read more about this, click here.) While other imaging methods such as EEG (electroencephalography) can measure this activity directly, they often come with severe limitations such as poor spatial resolution.  Instead, fMRI studies neural activity indirectly by measuring the BOLD (Blood Oxygenation Level Dependent) signal.  This method is based on the fact that hemoglobin carrying a bound oxygen molecule (oxyhemoglobin) in the bloodstream emits a different MR signal than oxygen-depleted hemoglobin (deoxyhemoglobin).  When parts of the brain become active, such as when a person is carrying out a cognitive task, they use up more oxygen than relatively inactive parts of the brain.  You might think that this would result in a relative decrease in the level of oxygen in the active areas compared to the inactive areas, but actually the reverse happens!  Because oxygen is being depleted, the brain compensates for the loss by increasing the flow of oxygenated blood to the active area.  There is a slight overcompensation, which causes an increased oxyhemoglobin to deoxyhemoglobin ratio.  As this ratio increases, the BOLD signal gets stronger.  Essentially the BOLD signal measures the ratio of oxyhemoglobin to deoxyhemoglobin in the brain, which enables researches to indirectly gauge neural activity: higher neural activity = higher oxyhemoglobin to deoxyhemoglobin ratio = stronger BOLD signal.

Advantages and Disadvantages of fMRI and MRI^

MRI and fMRI both involve no radiation, and there are no known side effects caused by the magnetic fields and radio waves.  The main risk with MRI is that the presence of metal in the body (such as pacemakers or other implants) can be a safety hazard.  fMRI is also relatively inexpensive, non-invasive, widely available, and provides excellent spatial resolution and good temporal resolution.  Largely because of these factors, fMRI has come to predominate in the field of neuroimaging research.

fMRI and Huntington’s Disease^

Use of fMRI or MRI scans in HD patients sometimes requires sedation since both techniques require remaining extremely still and the results can be ruined by small movements.  It is thought that fMRI can potentially be used as an indicator, or imaging biomarker, of early neuronal dysfunction in individuals before the onset of HD (a stage called pre-HD).  A 2004 study conducted with pre-HD patients demonstrated that fMRI could detect abnormalities in brain activity more than 12 years before the estimated onset of motor systems (Paulsen et al).  fMRI was also able to distinguish differences between patients closer to estimated onset and patients further away from estimated onset.  These results suggest that fMRI may be useful for tracking changes in neural function during the early stages of pre-HD, and could improve the prediction of when HD manifests in an individual.  The study also suggests that fMRI can be helpful in determining the optimal time frame of treatments aimed at slowing down the progression of HD.  However, further research is required to determine whether the potential of fMRI technology will be realized.

Positron Emission Tomography (PET)^

Positron emission tomography is a technique that uses radioactively labeled molecules (called tracers) that are injected into the bloodstream and taken up by active neurons.  PET studies blood flow and metabolic activity in the brain and helps visualize biochemical changes that take place.  Essentially, PET indicates how well the brain is functioning.

Public domain, Jens LangnerA PET scan of a human brain. (Public domain)

How PET works^

The scanner consists of a ring of detectors that surround that subject.  Detectors contain crystals that scintillate (give off light) in response to gamma rays, which are extremely high-energy rays of light.  Each time a crystal in a detector absorbs a gamma ray is called an event.  When two detectors exactly opposite from each other on the ring simultaneously detect a gamma ray, a computer hooked up to the scanner records this as a coincidence event.  A coincidence event represents a line in space connecting those two detectors, and it is assumed that the source of the two gamma rays lies somewhere along that line.  The computer records all of the coincidence events that occur during the imaging period and then reconstructs this data to produce cross-sectional images.

The tracer is usually a substance, such as a type of sugar like glucose, that can be broken down (metabolized) by cells in the body, and it is labeled with a radioactive isotope.  There is minimal risk involved since the dose of radiation is low and the isotope is quickly eliminated from the body through urination.  After it has been injected into the bloodstream, the isotope, which is very unstable, starts to decay, becoming less radioactive over time.  In the process it emits a positron (a positively charged electron).  When a positron collides with an electron, the two particles annihilate each other, producing two gamma rays with the same energy but traveling in opposite directions.  These gamma rays leave the subject’s body and are sensed by two detectors positioned 180 degrees from each other on the scanner, which gets recorded as a coincidence event.  A computer can determine where the gamma rays came from in the brain and generate a three-dimensional image.

As blood is more concentrated in activated brain areas than in inactivated ones, the scanner will detect more gamma rays coming from parts of the brain that are working harder.  On a PET scan regions of the brain show up as different colors depending on the degree of activity in those regions.  Yellow and red regions are “hot” and indicate high brain activity, while blue and black regions indicate little to no brain activity.

The brain function measured by a PET scan varies according to the type of radioisotope that is used.  For instance, oxygen-15 is used to study oxygen metabolism in the brain.  FDG, which is fluorine-18 attached to a glucose molecule, is used to study sugar metabolism in the brain.  Many more radioisotopes exist, and which one is chosen for a specific PET scan depends on what type of brain function a researcher desires to study.

Advantages and Disadvantages of PET^

PET, unlike other imaging tests, is able to detect irregularities in body function caused by disease, which often occur before anatomical changes become observable.  The quality of a PET scan is not affected by small movements, so the subject does not have to remain as still for a PET scan as they would for a fMRI or MRI scan, both of which can be ruined by small movements.

A main setback to PET is that it affords relatively poor spatial resolution, so the images may not be very clear.  Due to this, it is common for PET to be used together with CT or fMRI.  In addition, the use of radiation, even in a small dose, always involves a slight risk.

PET and Huntington’s disease^

PET scans are sometimes ordered by physicians as a follow-up to a CT or MRI scan in order to reveal any irregularities in brain processes.  They can be used as part of a more detailed diagnosis for HD, as well as in research related to abnormalities in metabolism and progression of the disease.   Nowadays PET scans are often combined with CT scans to provide images that pinpoint the location of abnormal activity within the brain; combined, these scans provide more accurate diagnoses than either performed alone.


CT, fMRI/MRI, and PET are three of the most popular techniques currently used for neuroimaging.  Each method comes with its own advantages as well as its own risks and disadvantages.  While neuroimaging is still a fairly new development in medicine and neuroscience, the discipline will likely continue expanding in the future, and will continue to provide valuable clinical applications and scientific insights about the brain.

Works Cited^

Paulsen JS, Zimbelman JL, Hinton SC, Langbehn DR, Leveroni CL, Benjamin ML, Reynolds NC, Rao SM. fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s Disease. AJNR Am J Neuroradiol. 2004 Nov-Dec;25(10):1715-21.

Further Reading^

FAQ about getting CT scans

A more detailed explanation of how MRI works
Additional information about fMRI

FAQ about getting PET/CT scans

J. Nguyen 4.9.12


Clinical Trials on Huntington's disease

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.

For more information on the different phases of clinical trials, click here.

All clinical trials have criteria specifying who can or cannot participate. There are many risks and benefits to participating in a clinical trial. For example, participants contribute to medical research, have access to medical care, and if assigned to the treatment group, are given new potential treatments throughout the trial. However, participants may also experience negative side effects as a result of participating, or they may receive a placebo. Clinical trials must follow strict ethical codes and are highly regulated to ensure the safety of participants as much as possible.

What is the Huntington Study Group?^

The Huntington Study Group (HSG) is an international non-profit group whose aim is to support clinical research of Huntington’s disease (HD). It was formed in 1993 and has members and research sites in the US, Canada, Europe, Australia, New Zealand and South America. The HSG often partners with pharmaceutical companies, private foundations, and government agencies to fund research investigating the effects and safety of HD interventions. (For more information on the HSG, click here).

Ongoing Studies that are Currently Enrolling Participants^


2CARE is a phase III trial that aims to study coenzyme-Q10 as a potential treatment for HD. For more on coenzyme-q10, click here. The study aims to measure the effectiveness of coenzyme q-10 in slowing the symptoms of HD and to study the long-term safety of administering the compound to people with HD. Previous studies have shown that coenzyme q-10 slightly slowed the progression of HD, but not enough to yield significant results. Compared to these previous studies, 2CARE uses a much higher dosage for a longer time period. To date, it will be the largest therapeutic clinical trial of HD, with expected enrollment of over 600 in the United States, Canada, and Australia. The study began in March of 2008 and is expected to be completed by April 2014. 2CARE is a double blind placebo study, in which participants are randomly assigned to one of two groups. The experimental treatment group will receive oral administration of coenzyme q10 in chewable form twice a day, for a total of 2400 mg/day. In a preliminary study called Pre2CARE, dosages ranging from 1200 to 3600 mg/day were tested; 2400 mg/day appeared to be the most effective dosage, as smaller dosages were not as effective, and larger dosages resulted in the mildly unpleasant side effect of upset stomach. Researchers will compare total function capacity (TFC) scores, tolerability, adverse events, vital signs, and laboratory test results between the two groups.


The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester are currently conducting a phase III clinical trial to assess the effects of creatine supplements on slowing the progression of symptoms in HD patients. Creatine is a molecule naturally produced in the body and consumed in the diet, found mostly in meat. Previous studies conducted on transgenic mouse models have shown that mice supplemented with creatine displayed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. The study is called the Creatine, Safety, Tolerability, & Efficacy in Huntington’s disease (CREST-E). Participants are randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study is a fairly large clinical trial. It will involve 44 research centers from around the world and enroll up to 650 participants. The study will last 37 months and is estimated to be completed in December of 2014. (For the most updated information on this study, click here).


Earlier in 2009, the HSG received funding from the NIH to test the safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not yet show any motor symptoms. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonELeading to preventive trials) and is a phase II trial. The study will be conducted at 10 clinical sites throughout the nation and is the first therapeutic research study in pre-manifest HD patients. Participants will be randomly assigned to experimental groups receiving 600, 1200, and 2400 mg/day of coenzyme q10. The principal investigators hope that this initial trial will lead to later trials that study the delay of HD.

Ongoing Studies that are No Longer Enrolling Participants^


ACR16 is a dopamine stabilizer and can enhance or inhibit dopamine controlled functions. For more information on the role dopamine plays in HD, click here. The HSG is conducting a phase II clinical trial testing different doses of ACR16 on HD patients age 30 and older. HART is sponsored by NeuroSearch Sweden AB, a biopharmaceutical company, and is being conducted in 35 research sites across North America. Previous studies showed that ACR16 is safe and tolerable in patients with HD and Parkinson’s disease. Additionally, it has been shown to significantly improve patients’ voluntary and involuntary movements. Participants are randomly assigned to one of four groups-three experimental groups given different doses of ACR16 and a placebo group. The study occurs over a course of 12 weeks. As of October 2010, results have been promising, as patients in the highest dosage group (90 mg/day) displayed significant improvement in motor function as measured by the modified Motor Score (mMS).

Recently Completed Clinical Trials^


HORIZON was a phase III clinical trial conducted by the HSG and the European Huntington’s Disease Network that investigated whether dimebon is safe and effective in improving cognitive abilities in patients with HD. Dimebon is an experimental drug that has been shown to prevent the death of brain cells in animal models and is currently being tested to treat HD and Alzheimer’s Disease. It is thought to work by stabilizing and improving function of the mitochondria. For more information on dimebon, click here. The study was conducted in various centers in the United States, Canada, Europe, and Australia. It was a double-blind, placebo study in which participants were either given 60 mg of Dimebon daily or a placebo. Results showed that dimebon is not effective in treating HD. There was no statistically significant difference in symptoms between the experimental and placebo groups. According to the president and chief executive officer of Medivation, development of dimebon in HD will be discontinued.


Minocycline is an antibiotic that is primarily used to treat acne and other skin disorders. For more on minocycline, click here. The goal of DOMINO was to assess whether minocycline was safe and effective in slowing HD progression and whether further studies should be conducted. The study is a phase II clinical trial that was started in 2006 and completed in November 2008 by the HSG with funding by the FDA Office of Orphan Products Development. It was a double-blind, placebo experiment in which participants were randomly assigned to a treatment group that received 100mg of minocycline twice daily or a placebo. The TFC scores of the two groups were then compared. Results showed that while minocycline was safely tolerated, it did not produce a significant effect in terms of delaying HD symptoms, and thus, further study of minocycline in treating HD is not warranted.


TREND-HD was a large phase III trial that began in September 2005 and was completed in August 2007. The goal of the study was to determine whether ethyl-EPA (Miraxion) slowed the progression of motor decline in HD patients. Ethyl-EPA is an omega-3 fatty acid commonly found in fish oil. Study participants had mild to moderate HD, meaning they displayed early signs of HD but were self-sufficient in daily living activities. For the first 6 months, the treatment group received ethyl-EPA while the placebo group received a placebo. For the next 6 months of the study, the placebo group was also given the active drug. Interestingly, there were no significant differences in Total Motor Scores between the two groups after the first 6 months of the placebo study. However, after the next 6 months in which all participants received the drug, the experimental group showed improvement as compared to the group that had initially received the placebo for the first 6 months. Further studies will need to be conducted to determine the efficacy of ethyl-EPA. There did not appear to be any safety concerns. After the study was completed, the investigators and sponsor of the study, Amarin Neuroscience Ltd., took the unprecedented step of telling the study participants about the results of the study by calling them and inviting them to a telephone conference regarding the study results. Study participants are typically not informed of the results of the clinical trials they participated in.


Huntington Study Group (HSG) and Prestwick Pharmaceuticals collaborated on a clinical trial. Called TETRA-HD involving tetrabenazine, a dopamine depletor. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD was a phase III clinical trial with the goal of determining the optimal dosage of tetrabenazine in treating chorea in people with HD. The trial was carried out at 16 different HSG sites in the United States, involving a total of 84 participants with HD. Fifty-four of the participants were randomly assigned to receive tetrabenazine for 12 weeks with increasing dosages over the first 7 weeks. The other 30 served as the comparison group and received a placebo. The results of the study indicated that tetrabenazine is effective in treating chorea with side effects that are less severe than those associated with other anti-choreic drugs. On the CGI Global Improvement Scale, 6.9% of the patients receiving placebo had more than minimal improvement compared to 45.1% of the patients receiving tetrabenazine. Clinical assessments showed that tetrabenazine was associated with drowsiness and insomnia in four patients, depressed mood in two, parkinsonism in two and akathisia in two. Most cases of adverse effects improved after adjusting dosage levels, but the risk of side effects should be considered. These results confirm the benefits of tetrabenazine usage in ameliorating the symptoms of chorea. In August 2008, the FDA approved tetrabenazine as the first drug for treatment of chorea, and it is used worldwide today.

For more information:^


-A. Zhang, 7-5-11 More

Studying Huntington's Disease

This chapter explains some of the many different types of research that scientists use to study Huntington’s Disease.

Fig Y-1: Transgenic Mouse Paw

The above figure shows a rather strange mouse paw photographed under fluorescent light. Why on earth is this paw green? Despite its appearance, the mouse is not an alien nor has it taken a bath in nuclear waste. Instead—and this also sounds crazy, but it’s true—the greenness comes from a special “fluorescence gene” that belongs to a jellyfish! When the mouse was just an embryo, scientists inserted this special gene into it and the gene became incorporated into the mouse’s DNA. When the gene then had its effects in the mouse, the resulting fluorescent protein caused the mouse’s whole body to light up, just as if it were still in the jellyfish.


You might be asking yourself: what could this green mouse possibly have to do with Huntington’s Disease (HD)? Although it is not clear from the picture, the mouse may actually have a lot to do with HD. Since a foreign gene is incorporated in its DNA, the green mouse is called a transgenic mouse. The fluorescence gene is just one example of a multitude of genes from many different animals that researchers are now adding into mouse DNA. One particular gene of interest is the human HD gene, which has been inserted into transgenic mice for research purposes for a number of years. These mice are part of the large field of animal research, a field that is teaching scientists important new things about HD.

Animal research is just one piece of the immense HD research puzzle. Other forms of HD research include family tree studies, epidemiological studies, genetic studies, postmortem studies, and clinical studies. Each of these areas of research has contributed a great deal to our current understanding of HD. More importantly, each of these areas will help contribute to the exciting breakthroughs in future HD research. These various areas of research, and some of the facts that they have already uncovered, are the subject of this chapter.

Animal Research^

  • Click here to learn about the basics of HD mouse models
  • Click here to view an article on the ethics of HD testing

Epidemiological Studies^

Epidemiology is the study of the spread of diseases within and between human populations. Similar to family tree studies, epidemiological studies involve finding which individuals show the symptoms of a disease and which do not. However, epidemiological studies differ from family tree studies in that epidemiologists generally study a greater number of people at one time. In fact, many epidemiological studies deal with the populations of entire countries, or even continents. In the case of HD epidemiology, researchers might, for example, dig through a country’s health statistics and find out how many individuals have been diagnosed with HD. These data can then be combined with other records—or perhaps with personal interviews if the individuals are willing—in order to reveal aggregate trends about HD in populations. For instance, one epidemiological study showed that five people per million get HD in Finland, as opposed to between 30 and 70 people per million in most other Western countries. Another study showed that the prevalence of HD among African Americans in South Carolina is only 9.7 per million, a strikingly low prevalence, and five times lower than the prevalence for Caucasians in the same area. These are just a few examples of the interesting findings of HD epidemiology. Since they tell us information about HD in populations throughout the world, epidemiological studies will be a vital piece in the HD research puzzle for many years to come.

Genetic Studies^

Fig Y-2: The Human Genome

Genetic studies seek to find a link between a particular gene (or genes) and a certain disease. If a genetic basis has already been established for a given disease, the studies seek to find the location of the gene(s) within the DNA. To do this research, geneticists depend heavily on data from family tree studies. They look at patterns of disease inheritance across generations of a given family, and, if possible, they supplement these data by studying the blood samples from living members. With regard to HD research, the most important question since HD was shown to have a genetic basis has been this: On which of the 23 human chromosomes is the Huntington gene located? (The 23 human chromosomes are shown in Figure Y-2). The most effective research to date to determine the location of the Huntington gene involves so-called “linkage studies”, as described below.

Linkage Studies^

Linkage studies use data from very large families with a history of HD. The principle behind linkage studies is that if nearly every person with HD in a single family shares the same version of a particular “marker trait,” such as the same color eyes or the same blood type, then the genes that code for that marker trait must be located close to the Huntington gene on the same chromosome. The marker’s gene and the Huntington gene are then said to be “linked” to one another. The logic behind such studies is straightforward—genes that lie close together on the same chromosome will tend to be inherited together over the generations. (Genes lying farther apart on the same chromosome are often not inherited together due to a complex process called recombination.)

In reality, eye color and blood type were not themselves useful as markers in HD studies, for their genes lie on chromosomes different from that of the Huntington gene. However, other markers were a tremendous help in locating the Huntington gene, including markers in a region of the Huntington-bearing chromosome called the “non-coding region.” The DNA in these regions does not code for proteins, but it still consists of a linear sequence of the chemical components called nucleotides. Using laboratory techniques, researchers found a few regions or “loci” of this DNA where family members with HD all had the very same nucleotide sequence. Since the researchers knew the locations of these particular loci, they were able to determine that the Huntington gene lies close by on the same chromosome. For example, a locus called “D4S90” had the same nucleotide sequence in every person with HD in a particular family. Since D4S90 was known to reside on chromosome #4, researchers concluded that the Huntington gene must lie along chromosome #4, very near D4S90. Data from other loci have confirmed this fact.

Once the location of the Huntington gene was identified through linkage studies, further genetic research (including linkage studies and other types of genetic investigation) revealed more details about the Huntington gene. With the cutting-edge technologies available today, it is likely that genetic research will continue to tell us a great deal about HD.

Human Postmortem Studies^

Human postmortem studies are carried out using the donated bodies of people who have died. In the case of HD, postmortem studies have been very important in locating the specific parts of the brain that HD affects. In comparing postmortem HD brains with non-HD brains, doctors have found that HD brains often show damage or decay in the basal ganglia, whereas no damage or decay is seen in the non-HD brains. (For more information about the basal ganglia and the affects of HD on the brain, click here). Postmortem studies also offer insight into some of the cellular events that take place in the brains of people with HD. For instance, by using very special staining techniques, postmortem studies have investigated the presence of nuclear inclusions (NIs) (For more information about NIs and huntingtin protein aggregation, click here). Understanding NIs and other cellular phenomena will be tremendously helpful in developing future treatments for HD. For this reason, postmortem studies are a very important type of HD research.

Family Tree Studies^

Family tree studies (also known as “pedigree studies”) have been a tremendously successful form of HD research throughout the years. This type of research involves looking at a large number of related individuals through several generations and searching for any disease-related similarities between them. Such research, combined with blood samples taken from living family members, allowed scientists to establish that HD is a genetic disease in the first place. For more information about the most famous family tree study on HD (conducted in the vicinity of Lake Maracaibo, Venezuela), click here.

Clinical Studies^

Clinical studies (also called clinical trials) are studies that involve human subjects with informed consent. In the case of HD, these studies have been critical in identifying the various symptoms that doctors now use to diagnose the disease (For more information on symptoms of HD, click here). In fact, the very name “Huntington’s Disease” comes from Doctor George Huntington, who was the first to notice that many of his patients’ symptoms were part of the same disease.

Now that the symptoms and typical age of onset of HD are clearly defined, clinical studies today are more geared toward judging the effectiveness of particular drug treatments. After a new drug passes the test in animal studies, the U.S. Food and Drug Administration requires that clinical studies be performed to ensure that the drug is safe for humans. Once approved by the Food and Drug Administration, drugs may be sold either as prescription drugs or over-the-counter drugs.

For more information on clinical trials, click here.

For further reading^

  1. Freeman, T. B.; Cicchetti, F.; Hauser, R. A.; Deacon, T. W.; Li, X.-J.; Hersch, S. M.; Nauert, G. M.; Sanberg, P. R.; Kordower, J. H.; Saporta, S.; Isacson, O. : Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proc. Nat. Acad. Sci. 97: 13877-13882, 2000.
    A technical paper regarding the transplantation of fetal neurons.
  2. Robbins, C.; Theilmann, J.; Youngman, S.; Haines, J.; Altherr, M. J.; Harper, P. S.; Payne, C.; Junker, A.; Wasmuth, J.; Hayden, M. R. : Evidence from family studies that the gene causing Huntington disease is telomeric to D4S95 and D4S90. Am. J. Hum. Genet. 44: 422-425, 1989.
    A technical paper regarding a particular linkage study that showed the Huntington gene to be located on chromosome 4.
  3. Mouse paw picture obtained from National Geographic web site (

Updated by T. Wang, November 2010


Animal Research: The Ethics of Animal Experimentation

Many medical research institutions make use of non-human animals as test subjects. Animals may be subject to experimentation or modified into conditions useful for gaining knowledge about human disease or for testing potential human treatments. Because animals as distant from humans as mice and rats share many physiological and genetic similarities with humans, animal experimentation can be tremendously helpful for furthering medical science.

However, there is an ongoing debate about the ethics of animal experimentation.


An Introduction to Animal Models of Huntington's Disease

Huntington’s disease research and drug testing frequently involve the use of mouse models. However, when different scientists refer to an HD mouse model they may not be referencing the same model. A variety of HD mouse models exist and are used regularly. This chapter will describe the most common HD mouse models, how they differ, and the ways in which they mimic the disease.

This article makes reference to both the mouse and the human huntington gene. The mouse huntington gene is a homolog of the human huntington gene, but there are subtle differences between them. For example, the mouse huntington gene has fewer CAG repeats than the normal human huntington gene, explaining why spontaneous mouse models of the disease do not exist. Despite this difference, the mouse huntington gene is 81% similar to the human huntington gene at the DNA level, showing that the two are true homologs. Different mouse models have been generated since the isolation of the HD gene in 1993. There are three general types of mouse model: knockout, transgenic, and knock-in.

Knockout models were the first models to be generated. These are models where the gene coding for the huntingtin protein (the mouse huntington gene) is removed or interrupted so that the DNA can not be transcribed. Although these models provide valuable scientific insights, they do not actually represent the disease because mice that are nullizygous for the huntington gene die during embryogenesis.

Transgenic models are made when the mutant human huntington gene, or a fragment of that gene, is inserted into the nuclei of a model organism. In transgenic models the gene insertion is not targeted to a specific location in the animal genome, meaning that where the gene inserts itself cannot be predicted. For a mouse model, this means that the mouse will express both the two normal copies of the mouse huntington gene as well as the human mutant gene or fragment that was inserted into its genome. It also means that the expression of the inserted mutant human huntington gene will not be controlled by the homologous promoter region of the mouse huntington gene. This frequently leads to much higher protein expression than normal endogenous levels.

Knock-in mice have either part of or the entire human mutant huntington gene inserted in place of part of or the entire endogenous mouse gene. Knock-in mice, therefore, carry the expanded CAG repeat mutation in the same place in the genome that it would appear if it were to develop naturally. This is the most faithful model in the sense that the mutant gene is located in the appropriate genomic context and will have the normal promoter region associated with the huntingtin protein. Knock-in mouse models can be either homozygous or heterozygous for the huntingtin mutation.

To learn more about the process of creating genetically modified model animals click here.

The remainder of this chapter considers the following topics:

More about knock-out mice^

Although knock-out mouse models are not a viable model of HD, studying these early models did increase understanding of the disease. Showing that a complete absence of the huntington gene, and consequently the huntingtin protein, was embryonic lethal revealed that Huntington’s disease is not a loss-of-function disease. The huntingtin protein is necessary for successful embryogenesis and when it is entirely absent the organism will die before birth. This suggests that the mutant huntingtin protein in individuals with HD must fulfill some of the same functions as the normal huntingtin protein.

Since most individuals with HD are heterozygous for the disease, they do still have one copy of the normal huntington gene and can express some levels of the normal huntingtin protein. However, HD homozygotes do develop normally and have an age of disease onset comparable to HD heterozygotes, confirming that the mutant protein fulfills some of the normal huntingtin protein functions. This suggests that HD is a dominant “gain of function” disease as HD patients are able to live with either one or two mutant HD alleles.

Some scientists suggest that despite the finding that HD is a gain-of-function disease, it is still possible that some loss of normal huntingtin protein function contributes to the disease. One study supporting this idea found postnatal brain degeneration in mice in which huntingtin was selectively inactivated in the brain and testes after early embryogenesis. Furthermore, another study found that normal huntingtin, but not mutant huntingtin, increases the production of brain-derived neurotrophic factor, which is necessary for the survival of striatal neurons in the brain. Although both of these studies support the conclusion that loss of normal huntingtin function contributes to the pathogenesis of HD, most researchers believe that HD should be considered a gain-of-function disease.

More about transgenic mice^

The earliest HD transgenic mouse models and still some of the most frequently used are from the line designated R6. In this model, a fragment encoding exon 1 of the human mutant huntingtin gene is inserted into the mouse genome. Four different R6 lines were established, with CAG repeat lengths ranging from 115-156. The R6/2 mouse, one of this line, is probably still the most commonly used HD mouse model. All four lines use the IT15 promoter. In humans it only takes a CAG repeat length of 36 or more to develop HD, but mouse models seem to need much larger repeat lengths to develop an HD-like phenotype, possibly due to their shorter lifespan.

Three of the R6 lines ubiquitously expressed the mutant huntingtin protein and exhibited an abnormal phenotype. The level of mutant huntingtin protein expression varied among these three R6 lines. The level of protein expression is usually represented as a percentage of the normal endogenous mouse huntingtin protein level. The R6/1 line had the lowest expression, measured at about 31% of endogenous mouse huntingtin levels. The R6/2 and R6/5 lines had an average expression of 75% and 77% endogenous mouse huntingtin levels. These lines displayed motor abnormalities such as chorea-like movements, weight loss, seizures, frequent urination, unusual vocalizations, and sudden deaths of unknown cause.

Newer transgenic mouse models now express longer fragments or the full length human huntington gene. One example is the YAC line. Mice from this line express the full length human huntington gene with a CAG repeat length of up to 128. These newer transgenic mouse models tend to show progressive motor abnormalities as well as neuronal loss in the striatum. These symptoms all closely parallel human symptoms in HD, and provide evidence that these mice might accurately model many aspects of the disease.

More about knock-in mice^

The first HD knock-in models did not display overt motor deficits like those observed in the first transgenic mouse models. Instead, they displayed some behavioral abnormalities such as increased aggression. The earliest models usually had between 70-80 CAG repeats. One reason that the early models did not reveal a phenotype resembling HD may be that they had a low number of CAG repeats for mouse models, which tend to have very high CAG repeat lengths.

Later knock-in models were more promising as they did show abnormal motor abnormalities, as well as cellular, molecular and neuropathological abnormalities suggestive of an HD phenotype. They also tended to reveal behavior abnormalities at earlier ages. These later knock-in models tended to have many more CAG repeats than the earlier models (from 94-140 CAG repeats).

Knock-in models are not all the same. Besides differences in CAG repeat length, there are also differences in how much of the mutant huntington gene is inserted and in the background strain of the mouse. In some models, only the sequence coding for the polyglutamine tract in exon 1 was replaced, while in others the entire first exon was replaced. The models that replace all of exon 1 with the mutant version should be more accurate representations of the human condition, because many of the proteins that interact with mutant huntingtin do so in the region immediately surrounding the polyglutamine tract. In other words, when a larger portion of the gene is inserted and it is expressed at an endogenous level, the mouse imitates the genomic context of the huntingtin mutation as well as the mutation itself, and consequently then phenotype may be more consistent with human HD. Most significantly, this means that any results found with these mice, either about relevant proteins, molecular pathways involved, or pre-clinical drug studies, are much more likely to be relevant to human HD.

Why do transgenic mice frequently display a more obvious disease phenotype?^

Transgenic mouse models sometimes seem to display a phenotype more similar to human HD than the phenotypes displayed by knock-in models. This might seem confusing since the knock-in models are theoretically more accurate representations of the disease genotype.

One reason for this unexpected result is that transgenic mice usually only express a fragment of the human mutant huntington gene. The mutation is then expressed as a truncated, or shortened, protein fragment. In vitro studies have founded the truncated protein to be more toxic than the full length protein, which could explain the more severe disease phenotype of these models.

In some transgenic models, this result could also occur because of unnaturally high expression levels of mutant huntingtin protein. Recall from above, for example, that HD line mice sometimes express as much as five times more mutant huntingtin protein than endogenous huntingtin protein. This overexpression could exaggerate the disease phenotype.

How are animal models used?^

Mouse models allow researchers to study aspects of the disease that would be impossible to do with human subjects. For instance, researchers can focus on changes in the brain or in cell-to-cell interactions during early stages of the disease with animal brain tissue. Mouse models are also a crucial part of early testing of potential therapeutics. Because mice have a shorter lifespan than humans, testing can be carried out much faster. Additionally, in the earliest stages of drug development it would be unethical to subject humans to the risks associated with the new drugs being tested.

Unfortunately, the use of mouse models in drug development does have some drawbacks. Mouse models of HD are not exactly the same as the human disease and there are also differences in how a drug will affect one species compared to another. Hopefully, as scientists develop more sophisticated models that better represent the genetics of human HD, model organisms will become more relevant for drug development and therapeutic testing. But it is always vitally important to keep in mind that drugs that look promising in animal models may not prove successful when applied to humans.

Further Reading^

– Adam Hepworth, 11-21-08


The HD Measuring Stick: Assessment Standards for Huntington's Disease




There are a number of well–established methods used to measure the severity and progression of Huntington’s disease (HD). These can evaluate a patient’s mental and physical capabilities and track any changes over time. Having standardized methods for measurement is important because it allows for the comparison of patients in clinical trials and the quantification of symptoms to guide treatment and therapy options.

Test Definitions^

Each of the tests measures the subject’s abilities to perform various mental and physical functions in different ways. The tests are often used together, providing a more complete picture of the patient’s physical and cognitive well–being.

It is important to recognize that the pages in this article are intended only to give general information about some of the different tests used clinically and in research. We do not recommend the self–administration of these tests. Accurate administration of these tests requires qualified personnel such as doctors, therapists, and other trained professionals.

Fahn Rating Scale (Physical and Mental)^

The Shoulson–Fahn functional capacity rating scale was first proposed in 1979. It measures independence in daily activities such as dressing, eating, managing personal finances, and engagement in occupation. Functional capacity in each category is ranked from Stage 1 to Stage 5, with Stage 1 representing the most independent level of function. The table below summarizes the scale as it was originally proposed:

Shoulson-Fahn Functional Capacity Rating Scale as Proposed in 1979
Engagement in occupation Capacity to handle financial affairs Capacity to manage domestic responsibilities Capacity to perform activities of daily living Care can be provided at
Stage 1 Usual level Full Full Full Home
Stage 2 Lower level Requires slight assistance Full Full Home
Stage 3 Marginal Requires major assistance Impaired Mildly impaired Home
Stage 4 Unable Unable Unable Moderately impaired Home or extended care facility
Stage 5 Unable Unable Unable Severely impaired Total care facility only

This table was adapted from Shoulson and Fahn, 1979. See further reading.

Unified Huntington’s Disease Rating Scale (UHDRS) (Physical and Mental)^

The UHDRS is a standardized rating system used to quantify the severity of HD. Used clinically and in research, it measures the patient’s abilities in four general areas: motor, cognitive, behavioral, and functional. The different portions of the test may be administered separately.

The following table summarizes the individual categories tested in the motor section of the UHDRS:

Skill Category Description
Ocular Pursuit the ability of the patient to follow a finger with the eyes in both the horizontal and vertical directions
Saccade Initiation the ability of the patient to turn the head in both the horizontal and vertical directions
Saccade Velocity the speed at which the patient is able to turn the head both horizontally and vertically
Dysarthria the presence of speech that is slurred, slow, and difficult to understand
Tongue Protrusion the ability to stick out the tongue and the speed to which the task is completed
Finger Taps the ability to tap the fingers of both hands (15 repetitions in 5 seconds is considered normal)
Pronation/Supination the ability to rotate the forearm and hand such that the palm is down (pronation) and to rotate the forearm and hand such that the palm is up (supination) on both sides of the body
Fist-Hand-Palm Sequence the ability to complete the sequence (making a fist, opening the hand palm down, and then rotating the hand palm up) more than 4 times in 10 seconds without cues is considered normal
Rigidity in arms the severity to which the range of motion of the arms is limited
Bradykinesia slowness in initiation and continuation of movements
Maximal Dystonia abnormal muscle tone (measured separately in the extremities, face, and trunk)
Maximal Chorea involuntary jerky movements of the body (measured separately in the extremities, face, and trunk)
Gait walking with normal posture
Tandem Walking the ability to walk in a straight line from heel to toe. The ability to do so regularly for 10 steps is considered normal
Retropulsion the ability to stand after being pushed back

In each category, patients are scored from 0 to 4, with 0 representing normal function, and 4 being the most severe dysfunction. The total score is the sum of the scores in the individual sub–categories. A higher UHDRS score indicates a more severe disease progression.

Zung Depression Scale (Mental)^

Patients with Huntington’s disease are significantly more likely to display signs of depression than people in the general population. Up to half of patients with HD demonstrate symptoms of depression. To learn more about the relationship between HD and depression, click here.

The Zung Depression Scale is a simple 20 item questionnaire. Patients judge statements about how they have been feeling on a qualitative scale ranging from “a little of the time” to “most of the time”. Each of the patient’s answers is then given a score from 1–4 and the sum of these scores is the total score. The range for total scores is between 20 and 80; patients with depression usually score between 50 and 69, while those with severe depression score above 70.

The scores and what they imply are summarized in the table below:

Score Indication
20-49 Normal
50-69 Depression
70+ Severe Depression

Mini–Mental State Examination (Mental)^

The Mini Mental State Examination (MMSE) assesses the overall cognitive status of patients. Its use is not limited to measurement of the progression of HD symptoms. For example, MMSE can also be used in the assessment of patients with other neurological diseases, such as Alzheimer’s disease.

It analyzes the patient’s abilities in 5 different areas of mental status: orientation, attention and calculation, recall, and language. Created in 1975, it is an effective 11–question test that only takes 5–10 minutes to administer and score. It has been used widely in both clinical practice and in research to measure the cognitive abilities of patients and subjects.


To test the patient’s orientation, he or she is asked what year, season, date, day, and month it is. He or she is then asked what state, country, town, hospital, and floor he or she is currently on.


Testing registration next, 3 objects are named, and the patient is given a chance to name all 3 of them. Assessing calculation abilities, patients are asked to count by 7’s.


Recall is tested by asking the patients to repeat the 3 objects he or she learned before.


Finally, language skills are tested in multiple parts. The patient is asked to name a pencil and watch, then is asked to repeat the phrase “No ifs, ands, or buts”. Next, he or she is asked to follow a verbal 3–stage command, and then a written command. Lastly, the patient is asked to write a sentence and copy the following drawing of two interlocking pentagons:


The successes and shortcomings of the patient are added up, and a total score is calculated. The maximum score on the MMSE is 30. Scores of 23 or lower are indicative of cognitive impairment.

Barthel Index (Physical and Mental)^

The Barthel Index (BI) is a commonly used scale to help assess the patient’s independence and his or her need for supervision or assistance. The test scores the patient’s ability to perform 10 basic daily living activities. Full credit for each criterion is not given if the subject needs even minimal help or supervision. The activities considered on this index include:

Scores for each individual item are given in increments of 5. The score for the items ranges from 5 to 15. The maximum total score is 100, and the higher the score, the more independent the patient.

Tinetti Scale (Physical)^

The Tinetti scale, also known as the Tinetti performance Oriented Mobility Assessment (POMA), is an easily administered test that measure’s a patient’s gait and balance abilities. The test takes approximately 10–15 minutes to complete and score.

The test is divided into two main parts, a balance portion and a gait portion. The patient’s balance in both the sitting and standing positions are measured. Additionally, the ability to stand from the sitting position and to sit down from standing up are quantified.

In the gait portion of the test, the subject is asked to walk across the room at a “normal” pace, and then back at a “rapid, but safe” pace. Various parts of the subject’s walk are noted, such as hesitation after being prompted to go, swing of the feet (height and path), step symmetry, step continuity, trunk sway, heel position, and smoothness of gait.

The test is scored on a 28 point scale. The indications for each score range are summarized in the table below. Scores ranging from 25–28 indicate a low fall risk, scores between 19 and 24 indicate a medium fall risk, and scores below 19 indicate a high risk for falls.

Score Indication
0-18 High risk for falls
19-24 Medium risk for falls
25-28 Low risk for falls

Physical Performance Test (Physical)^

The Physical Performance Test quantifies the subject’s performance in physical tasks. It is a standardized 9–item test that measures the subject’s performance on functional tasks:

Subjects are given two chances to complete each of the 9 items, and assistive devices are permitted for the tasks that require a standing position (items 6–9). Both the speed and accuracy at which the subjects complete the items are taken into account during scoring. The maximum score of the test is 36, with higher scores indicating better performance.

Symbol Digit Modalities Test (SDMT) (Mental)^

The Symbol Digit Modalities Test (SDMT) is a brief and simple mental test that takes less than 5 minutes to completely administer and score. The test measures the subject’s information processing speed and attention.

It involves a simple test in which numbers are randomly substituted for letters or geometric symbols. The subject is given a translation key, and is asked to translate them within 90 seconds. The task is easy for normal subjects to complete, but is more difficult for those patients with cognitive dysfunction.

The translation can be given in either a written or oral format. This flexibility in format allows for the testing of almost all subjects, including patients with speech or motor disorders. Additionally, the written format allows for the test to be administered to patients in a group setting.

Thurstone Word Fluency Test (Mental)^

The Thurstone Word Fluency Test (TWFT) is a simple test that measures the subject’s communication abilities. Given in either a written or oral form, the TWFT is commonly used to detect the presence of and define the nature of any cerebral dysfunctions.

First, the subject is given five minutes to write down or say as many words as possible that begin with the letter “s”. Next, he or she is given four minutes to list as many four–letter words as possible that begin with the letter “c”.

Several studies have shown that the TWFT is very accurate in identifying subjects with reduced cerebral function. However, the test is unable to identify which specific areas of the brain have been damaged. For example, the test can determine whether or not a patient has brain damage, but it cannot be used to detect whether the damage is on the left or the right side of the brain.

Despite its shortcomings, the TWFT is informative and is commonly used in combination with other tests to help gauge the presence and extent of brain damage in patients.

Stroop Test (Mental)^

The Stroop Test is a simple mental test commonly used to measure the subject’s attention and mental flexibility. It takes advantage of the Stroop effect, the interference that arises when the brain is presented with conflicting signals.

Patients are presented with a list of colors, like in the image below, each printed in a different color:

stroop test

Next, the subject is asked to name the color of each word rather than what the word is. For example, the correct response to the first word in the third column would be “red” not “blue”.

The subject’s accuracy and speed at the Stroop Test can be recorded and used to track the progression of cognitive disabilities.

Neuropathological Scales^

In addition to the tests discussed in this article, there are also various neuropathological grading systems which measure physical change in the brain as a result of the disease. One such scale that has been developed is the five–tiered pathological grading system, which rates damage done from Grade 0 to Grade 4, with Grade 4 having the most severe damage.

For further reading^

-A. Pipathsouk, 1-15-10


The Huntington's Disease Pipeline

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.

Basic 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.

Drug Optimization:
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^

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.

Drug Optimization^

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^

-J. Seidenfeld, 5/19/07