gene

The sequence of DNA that tells a cell how to make a protein.

 that causes HD was discovered in 1993. Since then, enormous progress has been made in laboratories throughout the world in understanding how the

gene

The sequence of DNA that tells a cell how to make a protein.

, and the abnormal

proteins

Complex molecules that perform a wide variety of activities in the cell.

 it produces —

huntingtin

The protein that causes HD.

 — cause brain cells to malfunction and die, causing the symptoms of HD.

These studies have taken place in cell models, animal models, in post-mortem human tissue and using human volunteers.

Treatments that slow down the disease in humans are still several years away, but the progress that has been made is very promising. The HD research community has expanded and organised dramatically, and there is much more funding available for HD research than there used to be. We believe a cure is possible, and we are united in working towards it.

gene

The sequence of DNA that tells a cell how to make a protein.

 causes disease has led to laboratory studies of HD animal models, in which experimental treatments have been shown to slow down the damage caused by HD — and even reverse it.

gene

The sequence of DNA that tells a cell how to make a protein.

 is “switched off” in a mouse model of HD — even after clinical signs develop — improvement can be seen in brain cells and clinical signs. This gives us reason to believe that, if we can introduce successful treatments in humans, patients may improve clinically, even after they have begun to experience symptoms of HD. [more]

gene

The sequence of DNA that tells a cell how to make a protein.

 (which is made from DNA) is like a recipe for the

huntingtin

The protein that causes HD.

proteins

Complex molecules that perform a wide variety of activities in the cell.

. When the

gene

The sequence of DNA that tells a cell how to make a protein.

 is switched on (transcription), a messenger molecule called mRNA is produced before the

proteins

Complex molecules that perform a wide variety of activities in the cell.

 is built by the cell (translation).

gene

The sequence of DNA that tells a cell how to make a protein.

 by telling the cell to ignore the mRNA. This can be achieved with specially constructed mRNA or DNA molecules, using techniques called RNA interference (RNAi) and antisense oligonucleotide therapy, collectively called

gene

The sequence of DNA that tells a cell how to make a protein.

 silencing therapy is already used successfully in human patients, for treating certain forms of high cholesterol and CMV retinitis (a viral eye infection). Trials of

gene

The sequence of DNA that tells a cell how to make a protein.

 silencing will soon be starting in motor neuron disease, a neurodegenerative disorder a bit like HD.

gene

The sequence of DNA that tells a cell how to make a protein.

 silencing is getting the molecules where they are needed. RNA and DNA molecules don’t enter the brain easily, and once there, getting them to spread through the whole brain is difficult. New methods of designing the molecules have greatly improved the efficiency of spread through the brain, and there are now devices that can deliver drugs directly into the fluid surrounding the brain.

Using these techniques, researchers have recently been able to slow down the progression of HD in mouse models.

gene

The sequence of DNA that tells a cell how to make a protein.

 silencing is very promising in HD because, unlike in many other diseases, the exact genetic cause of HD is known. Switching off the HD

gene

The sequence of DNA that tells a cell how to make a protein.

 may be a relatively simple way to prevent the many things that the mutation causes to go wrong in cells.

Before it can be tried in humans,

gene

The sequence of DNA that tells a cell how to make a protein.

 silencing therapy needs to be tested in HD model animals that have brains as large as a human brain, to test whether the combination of new molecules and new delivery techniques can get the treatment to where it is needed. It will probably also need refining to minimise any side effects of switching off the

gene

The sequence of DNA that tells a cell how to make a protein.

. [more]

huntingtin

The protein that causes HD.

 aggregates — the lumps of

proteins

Complex molecules that perform a wide variety of activities in the cell.

 that are seen in unhealthy brain cells in HD. Cystamine is converted into cysteamine by the human body. Cystamine has been tried in mice with HD and shown to slow down progression and improve movement. A trial of cysteamine was carried out in humans, and showed that it was tolerated quite well, but the trial was too small to tell whether the treatment slows down the disease. More trials are needed. [more]

autophagy

Pronounced or-TOFF-a-jee

 is a clearance process cells use to get rid of unwanted proteins. HD researchers think that the abnormal

proteins

Complex molecules that perform a wide variety of activities in the cell.

 in HD,

huntingtin

The protein that causes HD.

, is disposed of using autophagy. Looking for drugs that make autophagy happen more efficiently might help cells get rid of

huntingtin

The protein that causes HD.

 and live longer. Rapamycin belongs to a group of drugs called mTOR inhibitors, which activate autophagy, and it has been shown to slow down HD in a mouse model. However, rapamycin causes lots of side-effects in humans and when tested in patients, it was not shown to be effective. HD researchers looking for more efficient, less toxic activators of autophagy have identified several drugs that might be better than rapamycin, and these now need testing in animal models of HD. [more]

HDAC

Pronounced AITCH-dak

 stands for histone deacetylase, which is an enzyme involved in regulating which genes are switched on and which are switched off — a process known to malfunction in HD. Drugs called HDAC inhibitors — in particular one drug called

SAHA

Pronounced pronounced SAR-har

 — have been shown to be effective in slowing down the cellular damage in HD, and HD mice treated with SAHA have less severe disease. However, HDAC inhibitors, which are sometimes used to treat cancer, are toxic drugs with serious side effects. Researchers are looking for more effective HDAC inhibitors with less severe side effects, to try in humans. [more]

memantine

Pronounced MEM-an-teen

 is a drug sometimes used to help the memory symptoms of Alzheimer’s disease. It prevents excessive stimulation by a transmitter chemical called NMDA. Memantine has been suggested as a possible therapy for Huntington’s disease, to help with the symptoms and possibly to slow down the disease process. A couple of small studies have been performed, but so far the evidence on memantine is inconclusive. Further studies are going on in the USA into whether memantine is helpful in HD. [more]

proteins

Complex molecules that perform a wide variety of activities in the cell.

 (

huntingtin

The protein that causes HD.

) is cut into smaller

proteins

Complex molecules that perform a wide variety of activities in the cell.

s by enzymes called caspases. Some of the smaller fragments that are produced by this are more damaging to cells than the original full-length

huntingtin

The protein that causes HD.

. So, by turning off the caspases, the dangerous

huntingtin

The protein that causes HD.

 fragments might be prevented from forming. Minocycline is a drug that acts as a caspase inhibitor. Initially there was some optimism that minocycline might help in HD but so far no double-blinded, controlled trial (the most reliable kind of clinical trial) has shown evidence that minocycline is helpful in HD, but these clinical trials are underway.

There are 11 types of caspase, and caspase 6 is thought to be the one that generates the most toxic

huntingtin

The protein that causes HD.

 fragment. Work is underway to develop and test inhibitors of caspase 6 that might be more powerful than minocycline, but with fewer side effects. [more]

proteins

Complex molecules that perform a wide variety of activities in the cell.

 with many functions, but it’s known to be involved in energy production, the response to stress and controlling when cells divide. Recently, it has been shown that p53 accumulates in the brain cells most affected by HD, and that the

huntingtin

The protein that causes HD.

proteins

Complex molecules that perform a wide variety of activities in the cell.

 and p53 interact with each other. That means that some effects of

huntingtin

The protein that causes HD.

 might be due to abnormalities of the p53 pathway — or even that p53 controls levels of abnormal

huntingtin

The protein that causes HD.

.

Work is underway to identify targets in the p53 pathway that drugs might be able to alter, so that the negative effects of

huntingtin

The protein that causes HD.

 on cells can be minimised. [more]

apoptosis

Pronounced ay-pop-TOE-sis

 is the programmed death of cells — a form of cell suicide — that usually happens when a cell is so damaged, it is likely to do more harm than good by staying alive. Cells in HD patients’ brains are malfunctioning, and do undergo apoptosis, but it’s also possible that the abnormal

huntingtin

The protein that causes HD.

 is making cells undergo apoptosis earlier than necessary, so that relatively healthy cells die prematurely. HD researchers are looking for drugs that influence the cells’ decision to undergo apoptosis and help HD cells to live longer. [more]

gene

The sequence of DNA that tells a cell how to make a protein.

 but do not yet have any symptoms of the disease (carriers), will be essential to decide when to start treatment to delay progression and in monitoring their success.

One of the main aims of our work here in London is the identification of biomarkers that will be used to monitor the success or failure of possible treatments. Our blood biomarkers project, ICE-HD and LOOK-HD have been making progress towards finding biomarkers already. We are also participating in the international PREDICT-HD study of premanifest

gene

The sequence of DNA that tells a cell how to make a protein.

 carriers. Our newest study, TRACK-HD, aims to study all the possible biomarkers head-to-head in the most comprehensive biomarker study performed to date, to find out which combination of biomarkers is best — so that when HD-slowing therapies are ready to be tested, we will be ready to test them.