Huntington's Disease Drug Works


Extensive laboratory research and "preclinical" work must occur before testing of a drug or treatment for people with Huntingtons disease. For Huntingtons, this research included (1) the discovery of the gene in l993, followed by the (2) development of single cell models of Huntingtons disease which involved the placement of the Huntington gene into single cell systems like yeast (the same yeast that is used in bread making), all the way to specialized nerve cells. Scientists also put the gene into whole organism models including the fly, the worm and the mouse. HD researchers believe the mouse model (there are about 20 different ones) is the closest to the disease in humans.

Scientists use these various model systems to study disease mechanism, or how the mutant (or bad) huntingtin protein damages the cell. Through extensive study, they have shown that this mutant protein affects the cell at not one, but several different points in the biologic systems of the cell. They then try to find a treatment that would fit the biologic system they have identified: or in the science lingo, they target a drug to an active site. This type of testing is called "preclinical", the term used for all the work that goes into getting a drug or treatment from the research stage to testing in people.

Our scientists now have designed testing that uses yeast cells, nerve cells, flies, etc. that can screen hundreds of potential drugs for activity in slowing down or preventing the Huntington's disease process at one or more sites. When a drug candidate is found in these screens, chemists try to make it into a medicine that will have a better chance of working in people. For instance, for a drug to work in Huntingtons, chemists must make sure it can be gotten from the blood stream into brain cells.

The final step before testing a drug in people is to test it in mouse models of Huntingtons. It is very important that any drugs that look like they work in mice be "confirmed". This means repeating the mouse study to make sure the experiment really worked.


It is important to recognize the difference between testing drugs for use in Huntingtons disease that are already FDA approved and those that are still "experimental" or have not been FDA approved. FDA approved means that extensive testing has already been done, and that the Federal Drug Administration has given approval for its use. FDA approved means that a medical doctor can write a prescription for it now. This means that an already FDA approved drug could be used in people FIVE TO TEN YEARS EARLIER than a drug that is still experimental. This is a "near-term" drug candidate.

Even though a drug may already be FDA approved, it is still very important to test it for use in Huntingtons people. This is because we don't know that what works in a mouse with the HD gene will work in a person. Even if it does work, without human testing we won't know the best dose of drug to use, and insurance companies are not obligated to pay for it.

An experimental drug is a drug that has never been tested in people before, and therefore must go through a more intensive and time consuming process for federal approval. This process takes on the average another 5-10 years. These are much farther term prospect drugs.


Clinical trials are the process for testing drugs in people. This process can be divided into three phases.

PHASE ONE: Phase one studies test for safety. Already FDA approved drugs have gone through much if not all of this phase already and can often be combined with phase two. This saves a lot of time. For an experimental or non FDA approved drug this usually takes 20-100 healthy volunteers to make sure the drug causes no bad side effects. This phase studies how the drug affects different parts of the body. It also finds out what side effects occur if the dosage is increased. This phase is usually measured in months of time.

PHASE TWO: Phase two tests for best dosage. It can also give preliminary efficacy results and give early (but not conclusive) information about whether a drug will work. This phase of testing needs more people, in the range of several hundred people who have the disease. This phase is measured in months of time, but for a slow disease like Huntingtons, it may take years of time to be sure of best dosage.

PHASE THREE: After phase 2 studies suggest effectiveness in a small number of people, and best dosage is recommended, it goes to larger scale testing. Phase 3 tests include several hundred to several thousand patients. In this phase longer and more thorough testing of the drug's effectiveness is done. The full range of benefits or adverse side effects is studied. This is by far the most expensive phase.

After a successful phase three study: (1) if the drug is already FDA approved, the drug can be prescribed by any doctor. (2) If the drug is still experimental, a request for FDA review and approval must be accomplished before that drug can be prescribed. This adds another 5-10 years before a doctor can prescribe it.


The most common type of drug trial is the "double blind placebo controlled" one. This involves both the participant (you) and the investigator (the doctor) not knowing whether you as participant in the trial receive active drug or inactive (placebo control) pill. In the real trial the pills will look alike. However, in many of the prescription drugs useful in HD mice, the dosages required in people often cause side effects of nausea, diarrhea, etc. Some of the drugs have unpleasant odor or taste. In these situations, it is hard to effectively blind the participant or the treating investigator. Results from people taking active drug will be compared to those who took inactive "placebo" pills.

This kind of study tests for "average" results in a group of participants. For instance, if a drug worked very well in a few people, and not much in most people, the positive result would be missed.

This type of study usually gives the best scientific results, but requires large numbers (hundreds to thousands) of people. This kind of study works well in "common diseases" with large populations like diabetes or heart disease. It works less well in diseases that do not have large numbers of people (like Huntingtons). By its design, it also requires that some fraction of people participating in the trial get no active drug treatment. The Huntington Study Group Coenzyme Q10 study in people used this design, but didn't have enough people enrolled to know for sure whether it worked or not. Results can take years of time in a slow disease like HD no matter what the trial design.


Scientists sometimes need to use other types of clinical trial design for studies in diseases that do not have large numbers of patients. One such model is commonly used in cancer studies (particularly the more rare kinds). In cancer studies placebos are not often used. In this type of clinical trial each person is given a drug or drug combination. Response is measured by comparing to the expected (or historical) outcome.

In another type of small clinical trial design, (adaptive) different drugs are compared either in individuals and/or groups. An example of adaptive design for one person (n of 1) is similar to how a doctor uses drugs to treat a person with high blood pressure. In each patient with hypertension, the drug or drugs finally settled on for best treatment occur only after trying one or more till the best drug or combination of drugs are found. The best combination for an individual patient isn't known at the beginning. This is an example of a therapeutic trial.

Of course drug response measurement in hypertension is accomplished in weeks of time. In Huntington's, drug response measurement is much more difficult and will take months, perhaps even years of time. But the process would be similar.

This type of study would likely not get results any faster than the placebo controlled ones. However, the advantage of this type of study would be that each person participating would receive active study drug or drugs. Then if any of these drugs are successful, every participant has the advantage of being treated during the trial. This kind of trial also allows for add on of multiple drugs. It is likely that, at least with presently available drugs, multiple drugs will have greater effect than single drugs. This is certainly the case in the model mouse.

Further, small clinical trial design would test for individual response. After all, Huntington's is a complicated and highly variable clinical disease even if the initiating cause is one gene. So it is possible that a drug that doesn't work in one person with Huntington's will work in another. Individual therapeutic trials are much better than large trials in this situation.

This type of study would also allow not only for the add on of other available drugs, but would position participants for an experimental drug as it becomes available.

HDDW will utilize the small clinical trial design.