About HD Science

Even though the gene that causes Huntington’s disease was discovered in 1993, there’s still a lot to learn about how it causes disease. And there is still no treatment that can stop or slow down the progress of HD. The Enroll-HD study aims to help fill these gaps by supporting and accelerating HD research.

Open Questions

When people carry the HD gene mutation their bodies produce a misshapen version of the huntingtin protein (also called HTT) that makes some brain cells function poorly and eventually kills the cells. People are born with the gene, yet most are healthy for many years and only start developing symptoms in mid-life. Scientists don’t fully understand why it takes so long for the gene to make people ill, but it suggests that once we do have effective treatments there is a real possibility that this illness-free period can be prolonged. Every cell in the body produces the expanded huntingtin protein but the real damage is done in just one part of the brain, called the striatum. Researchers don’t understand why the damage is so specific, but it’s thought that the death of cells in the striatum of the brain leads to many of the major signs of illness. Surprisingly, it’s also still not completely clear what the healthy version of the huntingtin protein does, it seems to do lots of different jobs in the cell but its main purpose is not yet defined. To study these questions many scientists use animal models such as mice, rats, sheep or even flies that have been genetically altered to carry the HD disease gene. By working with animal models researchers can do more invasive studies, such as taking biopsies of brain tissue, that aren’t possible in people.

New Hopes

Research on the disease moved slowly for many years because HD affects a relatively small number of people. That has now begun to change. A number of promising new approaches are now being developed and some will soon be ready for testing in humans. One major aim of Enroll-HD is to support these new clinical trials of novel drugs that are being developed specifically for HD by helping to build the infrastructure needed to do clinical trials as quickly as possible. In this video "Postcard from Palm Springs 2014", HD family advocate and former NBC reporter Charles Sabine offers an overview of new HD research and discoveries presented at the 2014 HD Therapeutics Conference, hosted by CHDI in Palm Springs, California.

Now Under Development

Several new methods to lower the amount of mutant huntingtin in the body are now being studied. Many of them involve gene silencing, which are various ways to prevent the mutant gene from producing the disease-causing protein. These techniques are exciting because they are a whole new type of drug. Different versions of gene silencing might prevent or treat many different types of disease. For the most part, though, they are so new that they haven’t been widely tested in patients yet. One of these methods, antisense oligonucleotides (or ASOs), uses short stretches of DNA to zero in on the HD gene to prevent mutant huntingtin protein being produced, a so-called “huntingtin-lowering” strategy. In September 2015, the California biotech company Ionis Pharmaceuticals, in partnership with the Swiss pharmaceutical company Roche, began the first small clinical trial of huntingtin-lowering in people. This early-stage trial, with just 36 people, will explore whether the treatment is safe.

Another new drug has already moved on to larger trials: A phosphodiesterase inhibitor (PDE inhibitor). In general, PDE inhibitors change the activity levels of nerve cells. One drug, which inhibits a specific type of PDE called PDE-10A, was tested previously in people with schizophrenia, but evidence from mouse models suggests it might be more effective in HD. The pharmaceutical company Pfizer conducted a preliminary test of its PDE-10A inhibitor in a 28-day study of 37 people with HD. The drug seemed to be well-tolerated, without unexpected side effects or major safety worries. Even better, it seemed to improve volunteers’ performance on a test of motivation. Based on these encouraging results, Pfizer launched a bigger, more ambitious study. By the spring of 2016, its “Amaryllis” study, which will test the same drug for six months in 266 people, was fully enrolled, with all participants signed up.


For many diseases, especially those that affect the brain, there is a major need for biomarkers, which are indirect ways to measure what’s going on with the disease and where and how it is progressing. The mental and physical symptoms of HD can be very different in different people, which can be confusing for researchers testing a new treatment. A measurement that reflects the underlying disease process (such as how much mutant huntingtin is in a person’s brain) rather than only the signs and symptoms (such as how much chorea a person shows) would provide much clearer insights into the disease. In HD, some possibilities currently being considered include brain scans, mental and verbal tests, or proteins found in spinal fluid. Biomarkers are a major key to developing a drug that prevents HD. It can be difficult to measure whether a preventive drug works, since if it’s working nothing happens! If you have an accurate measure of how the underlying disease works and the drug causes a significant change in that measure, then you will have a pretty good idea that the drug is effective. That gives you the confidence to keep going with a clinical trial that will show that it actually helps people feel and function better (or keeps them from getting any worse). That takes longer but is the real gold standard of success.

Gene modifiers

People with Huntington’s disease have a mutant form of the HD gene that includes a region of DNA (the CAG repeat) that is longer than it should be. On average, people with longer versions of this gene (those who have more CAG repeats) develop symptoms earlier than those who have fewer. But you can’t predict when someone will become ill just by looking at how many CAG repeats they have. Even if two people have the same number of CAG repeats, one may develop symptoms much earlier than the other. Geneticists interpret that as meaning that the HD gene is not the only one that matters—other parts of your genome also play a role. The search for these gene modifiers has already identified a few that seem to be involved. Understanding how these genes influence the onset of HD might be a great clue toward finding a treatment to slow the progression of the disease. At the World Congress on Huntington’s Disease in 2013, Harvard geneticist James Gusella described this search.