When people carry the HD gene mutation, their bodies produce a misshapen version of the huntingtin protein (often abbreviated to HTT) that makes some brain cells function poorly and eventually kills those cells. People are born with the gene, yet most are healthy for many years and only start developing signs and 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 are looking to 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 and symptoms 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.

Huntingtin-lowering therapies

There are now some really exciting treatments in development for HD. 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, and some have already been tested in people with other diseases with promising results.

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. The recent Roche/Ionis phase 3 trial was evaluating an ASO approach, which had shown for the first time that a drug could lower huntingtin in people’s nervous system. Unfortunately that trial was stopped in March 2021, but this first demonstration that huntingtin can be lowered by a drug in people is hugely important; we will learn how we can do this safely with ASOs and improve their design.

There are now numerous other huntingtin-lowering therapies either in clinical trial in humans or soon to be, including a pill that can lower mutant huntingtin! You can learn more about these new drugs in the Postcards from Palm Springs.

Genetic modifiers

People with HD have a mutant form of the huntingtin 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 higher 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. This means that the huntingtin gene is not the only one that matters—other genes in your genome also play a role and modify the course of HD. Using blood samples from almost 14,000 people with HD (most of them Enroll-HD participants), the search for these genetic modifiers in genome-wide association studies (GWAS) has already identified several genes that seem to be involved. Understanding how these genes influence the progression of HD will provide big clues about how to develop drugs that will effectively slow down it down and give people much more disease-free time. Indeed some biotechnology companies have already developed new drugs to try and do this and are planning to evaluate these in humans very soon – learn more in the Postcards from Palm Springs.

One of the major aims of Enroll-HD is to support these 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 and as smartly as possible