HDBuzz (English)

Landmark study puts Huntington's disease trials on TRACK

feedback@hdbuzz.net (Dr Faye Begeti) — Thu, 9 May 2013 05:40:53 +0000

If we find a therapy that we hope can slow down Huntington's disease, how can we prove that it works in patients? What tests should we do and how long should we follow people up after treatment in order to see any real benefits? A major new paper from Sarah Tabrizi and colleagues, reporting the final outcomes of the TRACK-HD study, provides information that will help us better design trials of new therapies in HD as well as understand how the disease progresses.

Why do we need TRACK-HD?

Many Huntington's disease families will have become a little tired of hearing about drugs that are effective in animal models of HD - surely we want to cure people, not mice or rats or worms? But before we can successfully run more effective clinical trials in HD patients, we have to understand exactly what happens in people as they become sick.

Which signs of HD do we want to try and fix as part of a therapeutic trial? These kinds of questions are particularly challenging because, unlike diseases affecting other organs, it is hard to know whether drugs can really slow down disease process in the brain, hidden as it is within the skull.

That's where 'observational' studies come in. Observational studies are those in which patients are studied without giving them any treatments, simply to understand the disease process in great detail.

Led by Prof Sarah Tabrizi of University College London, the TRACK-HD study was designed to run like a mock drug trial. People carrying the HD mutation would be studied for a defined period of time (36 months), using a large array of measurements including brain scans, specialized motor measurements and examination by a physician.

What's just happened?

In a fourth successive paper published in top journal Lancet Neurology, the TRACK-HD team has just reported its final data, describing what they saw in people carrying the mutation after 3 years of observation. This timing is important, because it's a reasonable time frame for a real therapeutic trial. It lets us answer the question, 'if we had an effective treatment, could we test it in Huntington's disease mutation carriers in 3 years?'

There is a simple, hopeful, message that comes from this study, and that is that we now have better ways of doing clinical trials in HD. We know which specific tests are most sensitive to change at different stages of the disease process. As a consequence of this, we know how many individuals we would need to confidently see those changes as part of any trial of a therapy in HD patients.

How'd they do it?

TRACK-HD involved annual follow up of groups of people who've inherited the Huntington's disease mutation. Using well-established mathematical calculations that help predict when someone with the mutation will have symptoms of HD, people without symptoms of HD were divided into two groups: those who are estimated to be close to, or far from, disease onset.

The team also followed a group of patients in the early stages of HD and, for comparison, a control population who did not carry the HD mutation. Many of the control group are family members of the HD mutation carriers.

Of the 366 individuals enrolled, 298 completed the 36-month follow up. Not surprisingly, many participants that dropped out were in the more advanced stages of HD.

What'd they find?

Remember, the main goal of the TRACK-HD study was to determine which measurements best predict the onset of HD, and track its course after onset of symptoms. So what did the team observe for each of the groups in the study?

First, sensitive MRI brain scans, that are able to very accurately measure the shape and size of people's brain, could measure differences amongst every group in the study. Even the people predicted to be far from onset had specific areas of brain change during the 3-year duration of the study. Hopefully, all new studies of therapies in HD will include brain scans, so scientists can see whether this loss of brain tissue is prevented.

In the group of participants predicted to be far from onset, there was very little change in behavioral or other clinical measures during the 3-year follow up. These people seem to be coping fairly well with the changes in their brains observed by scanning.

However, over 36 months, participants predicted to be close to onset behaved rather differently. They started to show changes in a number of clinical tests, including a range of motor and memory tasks. As in the group predicted to be farther from onset, these behavioral changes were accompanied by changes in brain scans that reveal shrinkage.

Over the 3-year duration of the study, some of the participants who hadn't been diagnosed with Huntington's disease at the beginning of the study have now developed symptoms of the disease. This enabled the scientists to try and figure out which measurements predicted the transition from 'pre-manifest' to 'manifest'.

Several behaviors were useful in predicting onset of disease symptoms, including motor tasks such as finger tapping. Consistent with the idea that people with Huntington's disease have a hard time with empathy and emotional regulation, people who developed disease also demonstrated problems on an emotion recognition task.

What can we do with this information?

This study will help us to better pick tests to assess carriers of the Huntington's disease mutation who are closest to disease onset and in the early stages of disease. This will be important, as these are the groups most likely to be targeted for therapeutic trials.

It's important to note that the measurements described can't be used to predict disease onset for individual people - they only make sense when applied to groups of people, like in a clinical trial.

By using a combination of measures, from simple clinical tests to fancy imaging techniques, the authors ensured that in the future, the use of these tests could be rolled out across a large number of sites, which will make participation in any future trials logistically much easier.

We can now start to plan trials using the measures described. However, it is important to note that 'preventative' trials that aim to test treatments before symptoms onset will have to last quite long in order to see an effect: probably in the region of 36 months, if TRACK-HD is anything to go by.

Now, the crucial questions are what those therapies will be and how we can ensure that they actually do in humans what they do in cells or animal models of HD. For example, if we block mutant huntingtin production in cells or animals with 'gene silencing' techniques, how can we confirm that this treatment actually does what it's supposed to do in the brains of patients with HD?

One hopeful message from this study is that people who've inherited the mutation that causes Huntington's disease seem to be able to cope with it for quite some time. If we can develop therapies that help them fight off the negative effects of the mutation, we're hopeful that people could expect more healthy years, thanks to the remarkable ability of the brain to cope with damage.

Finally the investigators, patients and control subjects should be congratulated on their dedication to this intense study. Without their continued determination to see it through to three years, the study would not have been able to make such significant claims.

Splicing with danger: a new way of thinking about the harmful Huntington's disease protein

feedback@hdbuzz.net (Dr Tamara Maiuri) — Tue, 7 May 2013 23:10:25 +0000

Researchers are hard at work figuring out exactly how the expanded Huntington's disease gene causes harm. Recent work from a UK group has uncovered another clue to help solve the mystery. It turns out that faulty processing of the huntingtin 'recipe' produces a short, harmful fragment of the huntingtin protein.

The cookbook, the recipe, and the cherry pie

Huntington's disease is caused by an unwanted expansion of the huntingtin gene. But genes are made of DNA, and it's the expanded huntingtin protein that causes the problem. How do we get from DNA to protein? Via an intermediate messenger molecule called RNA.

It may help to imagine an overzealous recipe-guarding grandmother who keeps her cookbook locked in a vault so that it doesn't get damaged in the kitchen. Anyone who wants to make her famous cherry pie must go into the vault, make a photocopy of the recipe, and go out to the kitchen to assemble the ingredients.

In much the same way, our cells guard our DNA in the cell nucleus. RNA copies of genes are made in the nucleus, and transported out, where they are "translated" into protein. RNA messages act like recipes telling the cell exactly what ingredients to use to make the protein.

In the case of an expanded huntingtin gene, the RNA copy of the recipe is also expanded. The final protein has too many "ingredients" and isn't formed properly. Although we know that this expansion causes Huntington's disease, it is still not understood exactly how the expanded protein causes trouble in neurons.

The long and short of it

The huntingtin gene is very long - one of the longest genes we have - and stores the recipe for a very big protein. But the abnormal expanded region is right at the very start of the gene: the first line of the recipe, if you will.

One thing that researchers have noticed is that the brain cells of HD patients and mouse models contain very short versions of the huntingtin protein - only the first five per cent or so.

So how do these fragments come to be? Up until now, it was understood that special 'cleaver' proteins slice up the huntingtin protein, fragments of huntingtin.

Fragments that contain the abnormal expansion, though, are harmful to brain cells. Researchers led by Prof Gill Bates of King's College London suggested that there's another possible way these fragments could come about, and it occurs at the stage when the RNA copy of the recipe is made.

The cutting room floor

Recall that genes are made of DNA, which is copied into RNA, which is then translated into protein. Simple, right? But as with most things in nature, there is another layer of complexity to consider.

In fact, genes contain coding and non-coding regions that are arranged in sequence like a zebra's stripes. Only the coding regions of the gene end up as protein, while the non-coding regions are skipped out.

So in the process of copying the DNA into RNA, first a copy is made of the entire gene, and then the non-coding regions are removed from RNA, in a process called splicing.

If we refer to our grandmother's cookbook analogy, we can imagine that the cookbook has lines of gibberish inserted amongst the instructions. The whole recipe, with gibberish included, gets photocopied inside the vault, but the copy is cut up and stuck back together, without the gibberish, before going out to the kitchen.

So what's new?

Studying mice, Bates' team has found that the splicing step, where the non-coding gibberish is removed from the RNA message, goes wrong if the huntingtin RNA is expanded, as it is in Huntington's disease.

In normal mice, the non-coding region was spliced out properly and the first two coding regions were joined together correctly to form a sensible, full-length message.

But in mice engineered to carry an expanded huntingtin gene, the first non-coding region was not removed properly. Within this gibberish region lies a signal telling the cell to "cut this RNA short". As a result, mice with an expanded HD gene produce an extra, short RNA message made of just the first coding region and part of the non-coding region.

Once this short RNA message is translated into protein, the mice end up with a short fragment of the huntingtin protein, containing the expanded region: the very same short fragment that's thought to be harmful in HD.

The team looked at samples from human Huntington's disease patients. The abnormally short RNA message and protein were found in some, but not all of them. That may be because the production of the small fragments varies between different body regions or between patients.

How does the expansion in the RNA copy mess up the splicing process? Bates' team showed that a protein usually responsible for the editing of RNA message molecules actually sticks to expanded huntingtin RNA, but not to normal huntingtin RNA. It may be that this inappropriate sticking interferes with proper splicing, resulting in the faulty short RNA copy of huntingtin.

What do we do with this clue?

This study helps us to understand a new possible way in which harmful fragments of the huntingtin protein are generated.

Our brains and neurons are complex things, and this new mechanism may not be the only way through which harmful huntingtin fragments come about. The traditional 'cleaver' mechanism isn't ruled out by this new finding, and in fact both mechanisms may be happening at once.

What's more, harmful fragments are probably not the only way the expanded huntingtin protein does its damage.

But this new information is an important addition to our knowledge of how expanded huntingtin behaves in the brain. And the more we know, the better equipped we are to tackle the problem.

One possible implication of this work is for so-called 'gene-silencing' therapies for Huntington's disease, which aim to reduce production of the huntingtin protein, by sticking to its RNA message molecules and telling cells to get rid of them.

Until now, it was thought that all the huntingtin RNA in the cell was the full-length version. Researchers will have to bear in mind that some of the detrimental huntingtin protein may come from a shorter RNA message, which may be missed by some gene-silencing drugs.

Thankfully, since we've already seen gene-silencing drugs work in several animal models of HD, it's clear that this new research doesn't invalidate that approach. In fact, through improving our understanding, it gives us new ways of understanding how the HD gene causes Huntington's disease, and adds 'abnormal splicing' to our list of possible targets for solving the problem.

Proposed Huntington's disease 'biomarker' is not useful, new study suggests

feedback@hdbuzz.net (Dr Jeff Carroll) — Thu, 25 Apr 2013 09:49:29 +0000

A specific kind of damage called 'oxidative stress' may contribute to cells getting sick and dying in Huntington's disease. Previous reports had suggested that blood levels of a chemical marker of oxidative stress could be a 'biomarker' for HD clinical trials. But a newly-published work strongly suggests that it isn't a useful biomarker after all. Is this bad news?

Why we need biomarkers

Everyone working on Huntington's disease shares the goal of developing effective therapies for patients. To get there, we need to develop drugs. And to get drugs, we need to conduct clinical trials to test whether those drugs are effective.

But how do we know if a treatment is effective? What does it mean, to 'impact the course of HD'?

With some drugs, it's easy to tell they're working, because they clearly have a beneficial effect on symptoms of HD, like the movements associated with the disease.

Ideally, we'd like to go beyond symptoms, and find drugs that actually prevent, slow or stop the degeneration of brain cells that HD causes.

This is hard in Huntington's disease and other brain diseases, because we can't look at the brain directly to see whether the drug is working. A biomarker is something we can measure, that can give us a clue to what's happening in the brain.

Biomarkers are really important because they have the potential to speed up progress towards effective treatments. We want measurements that are reliable and simple to perform, and tell us about what's going on in the brains of Huntington's disease patients, without having to crack open their skulls.

If we had good biomarkers, we could use them to help determine whether a new drug was having a beneficial effect in a future HD drug trial.

Oxidative stress in HD

One of the waste products generated by all the cells of the body, including the brain, is a chemical called 8OHdG. The chemical name - 8-hydroxy-deoxy-guanosine - is a mouthful, but it's a pretty simple chemical to understand.

All of our genes are written in a chemical language that we call DNA. DNA itself is composed of 4 'letters', which scientists call 'bases'. One of these bases is called guanosine, which we abbreviate as 'G' when we talk about the genetic code.

If you'd like some trivia to impress your friends, you can point out that 'guanosine' gets its name from bird poop - 'guano'. The first unfortunate person to isolate guanosine did it using guano as a starting material.

Our cells are constantly undergoing all kinds of stress. One of the most important kinds of stress is called 'oxidative stress'. Basically, we need oxygen to power our need for energy, but it's a damaging molecule. And 8OHdG is a chemical that's produced when oxygen damages DNA.

In 1997, Dr Flint Beal of Weil Cornell Medical College led a team that observed increased levels of 8OHdG in the brains of people who'd died of Huntington's disease. This, and a large body of subsequent work in animals, led to the idea that HD is associated with increased oxidative stress.

Previous work

Based on these ideas about increased oxidative stress in Huntington's disease, in 2006 a group led by Drs Diana Rosas and Steve Hersch at Massachusetts General Hospital, Boston, looked at the levels of 8OHdG in the blood of HD patients who were participating in a drug trial.

What they found was very interesting - they found that HD patients had much higher levels of 8OHdG than the control subjects in the trial. In fact, more than three times more 8OHdG - a dramatic increase.

The drug the trial was testing was called creatine which, it was thought, might calm down oxidative stress. And indeed, dosing these patients with creatine appeared to reduce their levels of 8OHdG.

Based on the results of this relatively small and short trial, creatine is now being tested in as many as 650 HD patients, over for a much longer duration. That new trial, called CREST-E, will measure levels of 8OHdG in the blood, too.

So what does 8OHdG tell us?

More recent work has suggested that 8OHdG is not quite as useful as we'd initially hoped. For a biomarker to be useful, we'd hope to see changes in its levels before people become very sick with Huntington's disease. Otherwise, we won't be able to use the biomarker to run the trial that everyone wants to run - one which proves that a drug can prevent or delay the onset of HD.

In 2012, we saw work on 8OHdG from the scientists of the PREDICT-HD study. This observational study examines people who have the HD mutation, but not yet any symptoms of disease. These are the kinds of people that we'd like to treat someday, so looking for changes in this population is a really important first step for developing good drug trials.

Levels of 8OHdG were measured in the blood of PREDICT-HD participants. In this group, there were very subtle changes in the levels of 8OHdG. Complex mathematical analysis suggested that there might be an increase in the levels of 8OHdG in people carrying an HD mutation, but the change was very subtle.

More confusingly the PREDICT-HD investigators used two different technologies to actually measure 8OHdG and found conflicting results. One technology showed this subtle increase, and the other showed no difference at all.

New work to clarify the value of 8OHdG

This was confusing, and made it hard to know whether 8OHdG should be measured in HD patients as a biomarker.

In hopes of clarifying this issue, scientists from CHDI Foundation and the TRACK-HD study designed a new study, specifically focused on understanding what's going on with 8OHdG in the blood of HD patients and mutation carriers. Their work has just been published in the journal Neurology.

First, these scientists carefully tested how accurate their measurement technologies were. This is important, because without accurate measurements, no results can be relied on.

With a clear understanding of the preciseness of their tools, the team turned to 320 blood samples from the TRACK-HD study. This study has carefully examined people carrying the HD mutation over a three year period.

Using both measurement techniques, this careful study very clearly proves that there is no difference in 8OHdG levels in the blood of people carrying the HD mutation. The levels weren't up to begin with, and didn't change as the disease progressed. This means that levels of 8OHdG are not a good biomarker for HD trials.

So this is bad news, right?

This may sound bad - initially we thought 8OHdG might be a good blood measurement for HD drug trials, and now we know it's not.

But we actually think that this is very useful information. It's hard to make progress towards developing new biomarkers if we're still working on ones that don't work. Knowing that 8OHdG isn't useful enables us to focus our limited resources on more promising biomarkers.

This is how science is supposed to work! Science is cumulative, even when it seems negative. Every study builds on what we knew before, leaving us a tiny bit closer to developing the treatments and running the trials that lead to effective drugs for Huntington's disease.

Studies like PREDICT-HD and TRACK-HD have given us a huge array of potential biomarkers to follow up on. Ruling out one just means we're one step closer to finding one that does work.

Is access to predictive genetic testing for Huntington's disease a problem?

feedback@hdbuzz.net (Deepti Babu) — Tue, 23 Apr 2013 03:55:52 +0000

Is access to 'predictive' genetic testing for Huntington's disease a problem? Research from University of British Columbia researchers suggests that it is, at least in Canada. We explore the problem and possible solutions.

Predictive testing for the gene mutation that causes Huntington's disease allows people who know they're at risk to find out if they will develop HD later on. People who want predictive testing usually need to come to a specialist clinic in person, for several counseling appointments. But this and other reasons could be barriers that stop some from pursuing predictive testing altogether. To help understand these barriers and explore ways they could be addressed, researchers at University of British Columbia conducted interviews with 33 people who accessed predictive testing through their Center for Huntington's disease in Vancouver, Canada.

Predictive testing is offered worldwide, typically through a process following international guidelines. These guidelines, for which updated recommendations were recently produced, are designed to make sure that people thinking about getting tested have enough information and time to make whatever decision is right for them - whether they choose to opt for the test or not - and enough support throughout the whole process and beyond. Three to four appointments are recommended before testing, but it's clear that individual needs vary.

The team in Vancouver follows this process, but may adjust it so only one appointment happens in Vancouver. The remainder can involve the individual's local general practitioner, including receiving results.

Distance and inconvenience

Many of those interviewed said distance was a major barrier for them. Those in rural areas said it was difficult to take a variety of transportation (like an airplane, ferry or bus) to get to Vancouver for appointments.

Some study participants said that the long travel to Vancouver also meant missed work and family opportunities. Some study participants said they couldn't afford long travel for appointments, or couldn't take the time off work. Even though some rural participants were eligible for financial support and assistance in traveling to medical centers, some indicated that this didn't go far enough in covering overall costs.

Stressful travel and lack of support

Some participants, both far from and near to Vancouver, indicated the commute to the testing center was stressful. Sometimes the city rush-hour traffic meant a long commute home, even if the distance was not great. Still others said they felt too far from their family and friends, particularly when making the trip to and from Vancouver to receive their test results.

An inflexible and lengthy process?

Another major barrier study participants identified was the testing process itself. Specifically, many felt it was too rigid and not possible to tailor to an individual's specific circumstances and needs. Others commented they found the process was somewhat 'paternalistic', as if the testing center somehow knew what was best for them.

Some felt there were too many appointments, and could not understand why so many were required. As well, some participants said the testing process took too long. Including a waiting period for the first appointment, the testing process can take several weeks or months to complete (the exact time varies at each testing center). Many described this as difficult.

Receiving results and bringing a support person

Most interviewed felt they way results are delivered is a very personal preference, and most preferred to receive them in person. Some indicated they would have preferred for their general practitioner to give them their results, while others preferred to hear them from the testing center. Some did not like having to bring a support person to their results appointment. This follows the international guidelines, but some participants thought it was too restrictive and would have preferred to hear their results alone.

What are the take-home points of the study?

* In this Canadian population, there were two major barriers to those accessing predictive testing: distance and inflexibility of the current testing process. Of note, a large geographical distance is not always the cause - sometimes those living in the testing center's city can experience distance barriers.

* Barriers need to be addressed to help those who want to access predictive testing. Otherwise, people who want it may be put off predictive testing - or worse, they could access testing without proper assessment, genetic counseling and support. Addressing barriers promotes equity in healthcare, particularly in countries with socialized health care delivery. In an ideal world, predictive testing shouldn't be available only to those who can manage travel or taking time off work for their appointments.

* Many people do not understand the predictive testing process. Education about the process, and why it's structured how it is, can help people understand it, which in turn might make it more acceptable.

Does the study have limitations?

Since they only come from one area and one health system, these results may not apply to all health care regions. Those interviewed may not be representative of the population at-risk for Huntington's disease. Importantly, they had all opted to go through genetic testing. Further studies may be needed to determine why those who decide not to test make that decision, and whether these barriers, or others, are part of the reason.

Final thoughts

The recently updated predictive testing guidelines suggested two options to bridge distance if needed: telehealth (video-conferencing between two sites) and phone calls. The group in British Columbia is currently undertaking a study to evaluate telehealth for this use.

Those of us who specialize in seeing people for predictive testing for Huntington's disease meet regularly and are constantly evaluating our approach, as our colleagues in other countries do.

We do make adjustments to fit the needs of our population when needed. For example, we use a telephone call in place of some sessions. As well, we have used telehealth in situations where individuals were absolutely unable to travel to us with their support person. So far, this has worked well.

There is no "one size fits all" for every region that offers predictive testing for Huntington's disease, but research studies like this are important to learn about ways the process can be improved, and new approaches to consider.

HD Therapeutics Conference 2013 Updates: Day 3

feedback@hdbuzz.net (Dr Jeff Carroll) — Thu, 11 Apr 2013 10:40:54 +0000

Our third daily report from the annual Huntington's Disease Therapeutics Conference in Venice, Italy on the final day of the conference.

9:07 - Day 3 of the HD therapeutics conference starts with a session on the most exciting programs at CHDI, getting close to the clinic.

9:10 - Marg Sutherland of the National Institute of Health is describing the programs there directed at funding and supporting HD research. The National Institute of Health is supporting HD research to the tune of 54 million dollars every year!

9:27 - Margaret Zaleska from Pfizer is describing the pharma giant's work to develop an exciting new drug for HD. Pfizer's new drug ("MP-10") targets something called "phosphodiesterase-10A". In HD mice, MP-10 has a number of beneficial effects, supporting the idea that it might be useful for patients. Encouragingly, MP-10's beneficial effects in HD mice last longer than the drug, suggesting it might work on more than symptoms. Pfizer's completed its imaging trial in HD patients that was intended to help decide whether to go ahead with a drug trial. The answer: YES. Pfizer's trial will assess safety and tolerability in HD patients and will last 28 days with functional MRI imaging. Pfizer expects its drug trial in HD patients to start in 2014.

10:18 - Ladislav Mrzljak gives update on CHDI's KMO inhibitor research program. Inhibiting KMO should improve the balance of helpful and harmful brain chemicals in HD. CHDI's drug is called CHDI246. CHDI246 has been chosen as the lead candidate for its KMO-inhibiting properties but doesn't get into the brain very well - however, it does good things in the blood that then produce benefits for the brain. CHDI246 produces the kind of chemical changes we want to see in the spinal fluid of HD animal models. CHDI246 doesn't improve the HD mice. A bit of a surprise but may be because of fundamental differences between mice and people. CHDI's research questions whether JM6, a previously reported KMO inhibitor, works as the publication claims. Despite negative results in mouse trials, favourable chemical changes in primate tests mean CHDI wants to push ahead with CHDI246.

11:07 - Vahri Beaumont of CHDI is describing their work on "HDAC Inhibitors". Years of work from Gill Bates at King's College London suggests that blocking a specific HDAC - HDAC4 - helps HD mice. HDAC4 sticks to the mutant HD protein, but not the regular one. That's a hint that HDAC4 might be up to no good in HD. Getting rid of half of HDAC4 in HD mice make their neurons work much better, and helps them live longer. CHDI is working to develop a drug to block HDAC4 that could be taken as a pill. CHDI have identified several specific drugs that are potent inhibitors of HDAC4 and are testing them in mice. Beaumont tells us that early data shows blocking HDAC4 with a drug in mice doesn't show big improvements in HD symptoms in mice treated with it. So there's a lot of work to do to understand HDAC4 in HD.

11:56 - CHDI's Jonathan Bard gives an update on TrkB activating drugs (pronounced track-bee!). TrkB activators aim to mimic the 'nourishing' effects of the brain chemical BDNF. It keeps neurons alive and is reduced in HD. CHDI is also looking into delivering BDNF directly into the brain using a virus called AAV as a delivery truck. CHDI is testing two antibody-based TrkB activating molecules. Early results from the viral-delivered BDNF in mouse brain look good- it increases TrkB activity, as expected. Very early days for CHDI's TrkB and BDNF programs but looking good so far. These guys really know their stuff.

14:15 - Next up is the biomarker session, figuring out the best ways to measure and predict progression in HD to help tell if drugs work

14:20 - Beth Borowsky of CHDI presents work relating to a substance called 8OHdG, which has previously been reported as a biomarker for HD. 8OHdG is produced when DNA is damaged and a 2006 paper reported that it was increased in the blood of HD patients. Borowsky has led an incredibly careful multi-lab re-evaluation of 8OHdG in hundreds of blood samples. Borowsky reports that there were actually no differences in 8OHdG at any disease stage, or with progression within patients and 8OHdG is not a biomarker of HD state or progression. Rigorous 'replication' like this- carefully repeating others' findings - is an incredibly important part of science but seldom done. Borowsky says that the Track-HD study ran for 4 years and has identified the best imaging, clinical and cognitive (thinking) biomarkers. The latest data from Track-HD tell us that brain volume and other measures can predict how the disease may progress in future (It's important to note that these measures are not yet useful in individual patients, only when measured in groups). The next step is to use these measures to help run drug trials in HD patients

14:46 - Borowsky: CHDI also supports the CAB study developing optimised thinking tests for clinical trials in HD. 'Composite' cognitive scores, combining the results from several different tests, are probably the best. It's time to test our most promising biomarkers in a clinical trial.

14:52 - Borowsky announces CHDI's first human clinical trial - of aerobic exercise in Huntington's disease! The trial will primarily aim to validate the biomarkers we've developed over the last few years. But also whether exercise is good.

15:00 - Tiago Mestre gives an update on the Enroll-HD study, which is now active. Enroll-HD combines, updates and replaces the European Registry study and American Cohort study. Enroll-HD is an observational study- participants are studied but no drug is given. Enroll-HD aims to understand the disease, improve clinical care and enable clinical research (eg biomarkers and future drug trials). People who've tested HD positive or negative, people who haven't had a genetic test, and not-at-risk people can all take part in Enroll-HD. The aim is to recruit a third of the HD-at-risk population in each region where the study is running (North & South America, Europe, Australia).

16:07 - Carole Ho of Genentech gives an update on the Alzheimer Prevention Initiative. We must learn from other neurodegenerative diseases. Most cases of Alzheimer's disease are not caused by a specific mutation (like HD is), but some cases are. Recent Alzheimer's drug trials have disappointed, perhaps because the drug was given too late in the disease. However, focusing on the small number of patients with genetic forms of Alzheimer's enables treatments to be given much earlier. Now Genentech is starting trials of its new drug crenezumab in people with genetic Alzheimer's even before symptoms. Everyone with HD has the same basic genetic mutation, so preventative or very early trials would be possible. Good news for HD!. The Genentech drug wouldn't work for HD by the way, but we can learn from this way of doing trials. The FDA has recently relaxed its criteria for approving new Alzheimer's drugs, making it a little bit easier. The Alzheimer's trial will include the patients in Colombia whose genetic information was used to develop it - the HD community needs to remember and serve the Venezuelan families where HD is very common and whose DNA helped find the HD gene.

17:00 - The final speaker is Kenneth Marek of Institute for Neurodegenerative disorders, CT USA, an expert on 'molecular imaging' methods. Brain scans with names like PET and SPECT allow us to see the chemical changes in the brains of live human beings. Molecular imaging is already available to help diagnose Parkinson's and Alzheimer's by measuring buildup of harmful proteins. We don't yet have a way of scanning patients to measure levels of Huntingtin protein, but it would be very useful and its being worked on. However, other types of imaging could be useful for HD research, like one that measures PDE10, the target for Pfizer's HD drug.

Sunset conclusions

Tonight marks the end of this year's HD Therapeutics Conference, and we're saying goodbye to one another and to Venice. Leaving these meetings is always bittersweet - on the one hand, it's been a very stimulating few days of cutting-edge HD science, and we'll return to our work re-energized and fully informed. But at the same time, the inevitable challenges along the way remind of the difficulty of our task, and just how important it is to HD families that we're successful as quickly as possible.

Amongst this year's most exciting news is the rapid advancement of Pfizer's PDE10A drug, enabled by their collaboration with CHDI, towards human clinical trials. The HD mouse data presented here is among the most exciting that we've seen for any proposed drug. As well as looking like a very exciting drug candidate, the trials that Pfizer and CHDI have planned take advantage of everything we've learned from trials like TRACK-HD and PREDICT-HD, and will be the most advanced ever run in HD.

Gene silencing, too, received an exciting boost this week in the form of the announced multi-million dollar collaboration between biotech Isis and Pharma giant Roche to bring HD silencing drugs to the clinic. Like many scientists, we think that gene silencing is the most promising approach to developing meaningful therapies for HD families, and it's gratifying that large companies are willing to make a large financial investment in the therapy.

Developing treatments for HD is such a huge challenge that it's certain that some attempts will fail along the way. For example, some drugs that looked hopeful at early stages of development, including the 'HDAC4 inhibitors' from CHDI, now seem perhaps a bit less exciting than we'd hoped. Also, the failure of 8OH-dG as a 'biomarker' for HD means we have one less tool in our box for clinical trials. We'd encourage families to join us in thinking of these "failures" as positive developments - helping us focus on the most promising approaches.

The road to effective therapies for HD is long. While we are not at the end of this road yet, it's clear that we've made major progress along the path. The developments presented at this meeting leave us energized, excited and hopeful for the future of HD therapies.

HD Therapeutics Conference 2013 Updates: Day 2

feedback@hdbuzz.net (Dr Ed Wild) — Wed, 10 Apr 2013 16:17:48 +0000

Our second daily report from the annual Huntington's Disease Therapeutics Conference in Venice, Italy. You can tweet @HDBuzzFeed, comment on Facebook or use HDBuzz.net to send us questions, comments and queries.

9:09 - Good morning! Jeff and Ed will be posting updates from day two of the Huntington's disease therapeutics conference.

9:14 - Reminder for anyone who missed it: there's $30million in HD drug research that wasn't there last week - see our article on the Isis and Roche deal from yesterday.

9:17 - The first session is about the huntingtin protein: what is is, what does it do and how does it cause harm?

9:26 - Dr Hilal Leshuel of EPFL, France has cool ways of making proteins in the lab so they can be played with and studied. He has used these techniques to study a crucial Parkinson's disease protein, alpha-synuclein. He can artificially 'tag' his artificial proteins and see how cells handle them differently with different tags. Adding a tag called ubiquitin to the alpha synuclein prevents it sticking together into clumps (huntingtin does this too). Using techniques developed in Parkinson's disease, his lab can now study chemical modifications of the HD protein directly. Lashuel says that simple chemical modifications of normal HD protein can make it act like mutant protein - clumping together in 'aggregates'.

10:06 - Gerardo Morfini: HD patients have loss of 'white matter' in the brain, which is made of axons, suggesting it's important to understand. Morfini is studying axons from squid! They're huge, so much easier to work with than human or mouse axons. He has found that the mutant HD protein causes traffic jams in axons, slowing down traffic in neurons. He is looking for drugs that increase the speed of traffic in axons, combatting the effects of the mutant HD protein. Morfini wants to understand how 'axons' - the long part of neurons that transmit messages to other neurons - die in HD.

10:39 - James Surmeier is trying to understand which specific brain cells are the first to die in HD - what makes them so vulnerable? He is using cutting edge microscopes and techniques to study individual connections - synapses - between neurons in HD mice. He sees that communications between brain cells are improved with a drug which that is soon going to be tested in HD patients.

11:41 - Philip Gregory works with Sangamo, a company developing tools to actually edit the DNA of HD patients to remove the mutation. Gregory says that Sangamo is trying to refine their tools so that they can edit the mutant HD gene, while leaving the normal HD gene alone. Gregory says that editing mutant HD genes works in the brains of living mice, not just cells - good news for moving towards people.

12:10 - David Corey is working on new ways to "silence" the mutant HD gene. He wants to find tools for reducing levels of the mutant HD gene, while preserving the normal gene that has important functions. His team has three different chemical classes of drug that all do the same thing - help cells reduce levels of the mutant HD gene.

14:56 - We're now in the poster session, where over a hundred cool HD projects are being presented and discussed

16:18 - Dr Steve Goldman of the University of Rochester is giving the keynote address on new cell models for understanding Huntington's Disease. He tells us that until recently it was thought that the brain can't generate new neurons, but to a limited extent it can (at least in mice). We are beginning to understand how to direct the production of new neurons by the brain, even in HD mice. In HD mice, new neurons produced by the brain's own stem cells may appear able to replace lost cells to some extent. Goldman treated HD mice with virus-delivered instructions to make new neurons live longer than untreated mice (Goldman's work will be published soon in the journal "Cell Stem Cell" and we'll definitely be writing an HDBuzz article on it!). Replacing brain cells using stem cells from embryos was tried before but didn't work well, probably because we didn't understand how to look after the cells, nurture them to become neurons and get them to make the right connections when transplanted into HD brain. Goldman says we are now developing a better understanding of how cell transplants might work (but we're not ready for new trials yet). The brain contains many types of cells - neurons, which do the thinking, are the most famous, but there's loads of other 'support cells'. One type of 'support' cell is called astrocytes. Cells from human embryo injected into mouse brain can replace the mouse's own cells. In HD it might be good to transplant embryonic stem cells and hope they will replace the patient's HD astrocytes. Astrocytes help the electrical activity of neurons, so having healthy astrocytes could be good for an HD brain. Note that these human/mouse experiments haven't been tried in HD mice yet - just healthy mice so far. But innovative stuff. Goldman & others have better recipes for generating 'medium spiny neurons' from stem cells. Those are the ones that die early in HD.

18:12 - George Yohrling of the HDSA announces Human Biology Research Fellowship program. Funding for patient-centred HD research.

Sunset conclusions

It's the end of day two, and we're getting increasingly into the territory of ideas and approaches that are directly aimed at treating HD, now or in the future. We know from talking to family members how frustrating it is to constantly hear that treatments are getting closer, because all HD family members want to hear is that we have a treatment that works now. All we can do is echo the words of Robert Pacifici, CHDI's Chief Scientific Officer: "The drugs are coming".

Today we heard about many treatments, some very close to clinical trials, others more exploratory and experimental. Drug-hunters call this a "full pipeline" and it's a sign of a healthy, thriving research program with the potential to deliver drugs designed for HD that might actually work, and ought to keep getting better with each passing year. Tomorrow, in the final day of the meeting, CHDI's scientists will give eagerly-awaited updates on their internal programs pursuing some of the hottest targets for Huntington's disease therapeutics.

HD Therapeutics Conference 2013 Updates: Day 1

feedback@hdbuzz.net (Dr Jeff Carroll) — Tue, 9 Apr 2013 20:00:31 +0000

Our first daily report from the annual Huntington's Disease Therapeutics Conference in Venice, Italy. We'll be bringing you live updates via Twitter over the next two days. You can tweet @HDBuzzFeed, comment on Facebook or use HDBuzz.net to send us questions, comments and queries.

9:00 - Buonasera from Venice, where HDBuzz will be tweeting the latest Huntington's disease research news from the annual therapeutics conference

9:08 - Huntington's disease therapeutics conference kicks off with a session on systems biology

9:09 - Systems biology tries to understand networks of connected chemicals and processes, rather than focusing narrowly on one thing

9:10 - The hope is that this systems approach will help us better understand Huntington's disease and develop and test treatments

9:12 - Robert Pacifici of CHDI: one tiny change, the HD mutation, causes lots of changes in the biology of people who carry it

10:35 - Jim Rosinski of CHDI: new technologies are being used to get better understanding of HD, like RNA sequencing - what genes are on/off

10:38 - Rosinski: "Amazing things are possible now" and the HD gene gives us a head start for understanding the disease

10:38 - HD drug development company CHDI is integrating techniques from engineering and computer science to better understand HD

12:10 - Lesley Jones is studying HD mice to understand how much they look like HD patients. In many important ways they're similar.

12:16 - William Yang is using mouse brains to map out which proteins the HD protein interacts with. More targets for drug developers

12:29 - Collecting all this data from HD patients and animals poses computational challenges, that Steve Horvath is working hard to fix

12:43 - With nearly 300 researchers attending, this is the biggest ever HD therapeutics conference

14:33 - Why do we have an HD gene at all? Elena Cattaneo is studying diverse animals, including sea urchins, to try to understand

14:53 - According to Dr Cattaneo, the normal HD gene seems to have important roles during the development of the brain

15:10 - If the HD gene is important for brain development, what happens in brains of people born with the HD mutation? Peg Nopoulos studies this

15:11 - Nopoulos' HD-KIDS study follows school-age kids at risk for HD. Gene testing is done without anyone involved finding their result

15:14 - Nopoulos: major brain changes occur throughout childhood

15:19 - Nopoulos: KIDS-HD allows us to study not just HD but also the role of huntingtin in normal brain development

15:20 - Even in HD-negative people, there is variation in the number of CAG repeats in the huntingtin gene.

15:25 - In kids who don't have the HD mutation, some aspects of thinking and behavior are subtly influenced by CAG repeat length.

15:28 - Some brain areas are also affected by the number of CAG repeats in the HD gene - in kids who are NEGATIVE for the HD mutation.

15:29 - Fascinating insights into the core mystery of Huntington's disease from Nopoulos: what does the normal huntingtin protein do?

15:33 - In kids who DO carry the HD mutation, Nopoulos finds subtle changes that are compensated for, but are their brains more vulnerable?

15:50 - Audience question from statistician raises concerns that statistical methods used to test Nopoulos' data may not be rigorous enough for small sample

16:25 - Jeff Macklis of Harvard studies the neurons connecting brain's cortex (crinkly surface) to the basal ganglia (movement control bit)

16:44 - Macklis: understanding of how different cell types become neurons and how they function has improved dramatically in past 5 years

17:16 - Ali Brivanlou of Rockefeller University is an expert on human development. Huntingtin protein is found in the very earliest embryo cells

17:17 - Using RNA sequencing, Brivanlou has identified 4 new RNA message molecules for huntingtin in embryo cells. These could produce new proteins

17:18 - Brivanlou's 'new' huntingtin molecules are created by reading the huntingtin gene in different ways to create 'spliced' RNA messages

17:20 - The function of these new huntingtin forms in embryonic cells is not known. Remember we're talking about normal, not mutant huntingtin here.

17:31 - Brivanlou: Embryos without huntingtin die after a week of development, but why? It changes the response to growth molecules

17:34 - Brivanlou: huntingtin has an influence on the metabolism of embryos - that's how they use energy & do chemical reactions.

17:38 - Brivanlou: in embryos with the HD mutation, sugar metabolism is unexpectedly altered. It's unclear whether this affects development

17:43 - Today's biggest news: Roche & Isis sign $30million deal to take gene silencing drugs for HD to trials

Sunset conclusions

On the opening day of the biggest ever Huntington's disease therapeutics conference, we heard a lot about studying the complexities of the brain, and the role of the huntingtin protein, still mysterious twenty years after its discovery - but not very much about drugs. But understanding how the brain develops and works, and 'knowing the enemy' - the mutant huntingtin protein and its damaging effects - are both crucial if we are going to safely and rapidly develop the treatments we're all working towards. You never know where the next big idea will come from, and it's from fundamental, imaginative research of the kind we've hear about today that bright new ideas for possible treatments may well spring up.

Major Roche-Isis deal boosts Huntington's disease gene silencing

feedback@hdbuzz.net (Dr Ed Wild) — Tue, 9 Apr 2013 19:45:28 +0000

Isis Pharmaceuticals and Roche have announced a multi-million dollar deal to support the development of 'gene silencing' drugs to human trials. This is big news that secures the future of these exciting drugs for Huntington's disease.

If you ask a hundred Huntington's disease researchers what the most promising experimental approach to preventing and treating Huntington's disease is, nearly all would say 'gene silencing', also known as 'Huntingtin lowering' treatments. Now, a major deal between Isis Pharmaceuticals and drug giant Roche promises to support the development of one kind of gene silencing drug, called ASOs, taking them through to clinical trials in patients as quickly and efficiently as possible.

What's gene silencing?

The cause of Huntington's disease is the protein huntingtin, which is made throughout the body. Huntingtin is useful, but in HD, an abnormal form of the protein called mutant huntingtin causes damage, kills neurons and eventually produces the symptoms of the disease.

The instruction set for making the huntingtin protein - the huntingtin gene - is stored in every cell and is made of DNA. To make a protein, the cell first manufactures a working copy of DNA, from a related molecule called RNA. That 'message molecule' is then read many times by the protein-making equipment of the cell, which churns out lots of copies of the protein.

This RNA message molecule is the target of gene silencing drugs. The drugs are made from chemicals similar to RNA, and are designed to stick to the huntingtin message molecule but not to other message molecules. Once stuck, the drug tells the cell's own machinery to dispose of the message molecule, so the protein isn't made. That's why gene silencing is also called huntingtin lowering.

There are different options for exactly what the drug molecules are made from, and several teams across the world are developing and testing different approaches.

So far, we've seen gene silencing drugs tested in several different animal models of Huntington's disease, successfully delaying symptom onset or even reversing symptoms. These groups of researchers are now racing to hone their drugs and begin human trials.

Isis and ASO drugs

Anti-sense oligonucleotides or ASOs are one type of gene silencing drug, made from a DNA-like chemical. Isis Pharmaceuticals is the main driver developing ASO drugs for Huntington's disease.

The main advantage of ASO drugs is that they naturally spread quite well through the brain when injected into the spinal fluid. In contrast, other gene silencing drugs with names like RNA interference, siRNA or shRNA, need to be injected directly into the substance of the brain and don't spread very far without help.

Last year, Isis announced successful safety trials of an ASO huntingtin gene silencing drug in primates, a crucial step on the road to getting a drug approved for human trials. Right now, Isis is at the stage of honing its drugs and deciding which one is best to take forward.

A pretty big deal

Developing 'designer' drugs is hard, and expensive, and testing drugs in human patients is the most expensive part. A fairly small company Isis would be unable to afford the huge cost of further development on its own, even with the support of existing partners like the CHDI Foundation. That's why the newly announced deal with Roche is big news.

Essentially, Roche has committed to paying Isis $30 million for the development of its Huntington's disease drugs and the first 'phase 1' clinical trial in patients. If that goes well, Roche will pay up to $362 million to further support the development and licensing of the drug.

Beyond the money, the deal also gives Isis access to the significant resources and technologies of Roche. One exciting future possibility is Roche's brain shuttle technology, which aims to get the drugs into the brain without having to inject them into the spinal fluid.

Turning off one or both?

Every person has two copies of the huntingtin gene, one inherited from each parent. In most cases, Huntington's disease is caused by just one faulty copy of the gene. Meanwhile, the normal copy of the gene produces a protein that does useful stuff and doesn't cause harm.

Isis's drugs that are closest to human trials target the message molecules from both copies of the gene - mutant and normal. So far, the early indications are that this approach is successful without causing harm. In part, that's because neither copy of the gene is 'silenced' entirely.

But Isis is also working on drugs that only silence the mutant copy of the gene, reducing the potential for side effects. This is called allele-specific silencing. That's a surprisingly difficult thing to do, because the place where the mutant gene is different isn't necessarily the best place for a silencing drug to stick. So the drug-hunters have to look for other small differences between the two copies.

We don't yet know what approach to gene silencing will be best, so it's good to know that the deal will support both options.

Timelines

While it's great to hear that a big pharmaceutical company like Roche is willing to commit such large sums of money to a Huntington's disease drug, the big question for HD families is when clinical trials will begin in patients.

Both companies are understandably reluctant to commit to a specific deadline. In a conference call, Stanley Crooke of Isis said that "'A little while' is as precise an answer as I'm comfortable giving today". Safety is paramount: it's essential to get the drugs as good as possible and test them thoroughly before taking the risk of giving them to a human.

But it's clear both Roche and Isis want to move forward as quickly as possible, and thanks to this huge deal, they now have the combined resources to make this happen.

Lost in translation? New insights into the making of the Huntington's disease protein

feedback@hdbuzz.net (Dr Melissa Christianson) — Mon, 1 Apr 2013 04:45:47 +0000

Everyone has two copies of the huntingtin gene but Huntington's disease is caused by a copy that's extra-long. New research shows that cells have different controls for how the normal and extra-long instructions are used to make protein. These controls on the protein-making process may be targets for developing drugs for HD.

You say potato...

We've known for twenty years now that the cause of Huntington's disease is a mutation in the huntingtin gene. In people who develop the disease, one of the two copies has a repeated section that makes the gene extra-long.

By analogy, if we were to write the normal huntingtin gene as the word 'potato', patients with HD would have one copy of huntingtin misspelled as 'potatato' or even 'potatatatato'.

It's the extra-long copy of the huntingtin gene that makes neurons sick, because it causes them to produce an extra-long, harmful version of the huntingtin protein.

One problem facing scientists is to develop treatments that reduce the harm done by the extra-long protein, while preserving the useful functions of the normal-length protein. That's not easy to do, because the proteins are identical except for the repeated section. However, some new research by a German team, published in the journal Nature Communications, has shed some new light on this problem.

The making of a protein

To understand this new research, first we'll need to cover a few details about how cells actually make proteins.

The life of every protein starts off the same way, as a set of instructions written in the genetic code of the cell - our DNA. First, the cell makes a working copy of the DNA, made from a related chemical called RNA. This copying process is called transcription.

The RNA instructions float around the cell until they encounter a structure called a ribosome. When the instructions pair up with a ribosome, the ribosome uses them to assemble a protein. That process is called translation.

You can think of translation kind of like what happens when a chef prepares his world-famous chili: the chef (the ribosome) uses his favorite recipe (the RNA instructions) to make the chili (a protein).

Just like a chef sometimes has the help of an assistant chef when making his cuisine, ribosomes sometimes get a little bit of help making proteins. In these cases, the ribosomes join up with special helper complexes in the cell. The helper complex lets the ribosome translate genetic messages into protein more quickly than the ribosome could on its own.

A little help from my friends

With these details of translation in mind, a team of Huntington's disease researchers, led by Susann Schweiger of The Max Planck Institute for Molecular Genetics in Berlin, decided to study how huntingtin proteins are made from genes of different lengths.

As expected, they found that the normal and extra-long genetic instructions were both translated into huntingtin proteins when they met up with a ribosome (the chef from our analogy above).

During translation, however, the RNA instructions for extra-long huntingtin can also interact with a helper complex (the assistant chef from our analogy). This interaction wasn't seen with normal-length huntingtin RNA.

It turns out the the longer the RNA instructions are, the more they can interact with the helper complex. Because the helper complex makes translation more efficient, the result of this interaction was that the cells made more extra-length than normal-length huntingtin protein.

Lost in translation: reducing levels of extra-long huntingtin

The scientists wondered if they could affect levels of normal and extra-long huntingtin protein just by interfering with the helper complex.

Since the helper complex mostly interacts with the extra-length huntingtin instructions, interfering with it should reduce translation of the extra-long variety.

When the researchers blocked the helper complex using drugs, or prevented cells from making the helper complex in the first place, they got the result they expected - less of the extra-long huntingtin protein was made.

Decreasing extra-long huntingtin levels this way is appealing, because it happens before the protein ever gets made. If we could do it in people, it'd mean that extra-long or 'mutant' huntingtin would never even have a chance to make neurons sick.

Does this affect the search for HD treatments?

This research shows one effective way to alter production of normal and extra-long huntingtin selectively. It would be a form of 'huntingtin lowering' or 'gene silencing', but one that doesn't rely on DNA-like or RNA-like drugs, which are difficult to deliver to the brain.

In addition to the helper complex itself, scientists are also looking at targets that work further down the protein production line.

One such target is mTOR - a protein that is actually already on the scene as a potential target in Huntington's disease therapy.

We've known for a little while that drugs that interfere with mTOR decrease levels of mutant huntingtin protein by helping cells destroy it after it's made. The new research shows that these drugs may pack a second punch, too, by decreasing the amount of extra-long huntingtin that gets made in the first place.

mTOR is particularly tantalizing as a drug target because the FDA, which regulates which drugs can be used in humans, has already approved some mTOR inhibitors for cancer treatment and in organ transplants. If interfering with mTOR really is an effective treatment strategy, drugs that already exist could be repurposed for use in Huntington's disease.

Should we pop the champagne?

Not yet! First off, all of this new research on the role of the helper complex and mTOR in making extra-long huntingtin protein was done in cells or mice. These laboratory models are only the first step in understanding the human disease, so a lot of work remains before we'll know if these pathways are actually important for real people with Huntington's disease.

Second, even if these pathways are important, the other effects of drugs targeting these pathways may make it difficult to use them in Huntington's disease.

For example, the FDA-approved mTOR inhibitors described above work because interfering with mTOR is toxic and suppresses the immune system. That makes the drugs effective against cancers and for preventing transplant rejection. But since mTOR inhibitors would need to be taken for many years in Huntington's disease, these effects may make them unsuitable as HD therapies.

The bottom line

This work is a fascinating new approach that's moving Huntington's disease research in the right direction. The more we understand about how the normal and extra-long huntingtin proteins are made and work in brain cells, the better equipped we'll be in the search for HD treatments.

Simple rules for a good night's sleep in Huntington's disease

feedback@hdbuzz.net (Prof Jenny Morton) — Mon, 25 Mar 2013 14:27:34 +0000

In part two of our special feature on sleep problems in Huntington's disease, we bring you Prof Morton's 'simple rules for a good night's sleep', distilled from her comprehensive review of sleep research in Huntington's disease.

Simple rules for a good night's sleep

In the first part of this special feature on sleep, Prof Morton reviewed what's known about sleep problems in Huntington's disease. Problems with sleeping and loss of normal daily rhythms in HD are common but potentially manageable. Here, based on what's known about sleep disturbance in HD, as well as advice that comes from sleep research more broadly, we are pleased to present Prof Morton's simple rules for a good night's sleep.

The rules are reproduced here by kind permission of Elsevier Science, from A. J. Morton, 'Circadian and sleep disorder in Huntington's disease', Experimental Neurology 2012.

As ever, this extract is provided for information only, and that HDBuzz is not a source of medical advice. If you are having problems with sleeping, you should see your doctor.

Bedtime and napping

* Set a bedtime, and go to bed within 30 minutes either side of this time.

* Fix a 'wake-up' time that is 8 h after your set bedtime. Note that you will probably need to set an alarm to wake you up. You must get out of bed when the alarm goes off, even if you still feel tired. It will probably take a couple of weeks to get used to your 'going-to-bed' and 'wake-up' times. Stick to your going-to-bed and wake-up times, even at the weekends, until your sleep patterns are consolidated.

* Establish going-to-bed patterns of activities that will help you to sleep (see below, 'Getting ready for bed').

* Avoid taking naps during the day. If you feel sleepy, do something else. Go for a walk, do the dishes, take a shower. If you must take a nap, limit it to 30-40 minutes and set your alarm clock to wake you up.

Exercise

Take a regular bout of exercise during the day, but don't do strenuous exercise within 2 hours of bedtime.

Food and drink

* No coffee more than 4 hours after your wake-up time. (For example, if you get up at 7 am, you should not drink coffee after 11 am.)

* No alcohol within 2-3 hours of bedtime. (If you go to bed at 11 pm, ideally you should not drink alcohol after 8-9 pm.)

* Try to eat your last full meal at least 4 hours before bedtime.

* Have a light snack before you go to bed. Foods that are rich in tryptophan may be helpful. These include milk, yogurt, eggs, meat, nuts, beans, fish, and cheese (Cheddar, Gruyere, and Swiss cheese are particularly rich in tryptophan). Try warm milk and honey or bananas.

* Avoid smoking or chewing tobacco for at least 1-2 h before bedtime. If you smoke, cut down on cigarettes/tobacco. Nicotine is a potent drug that speeds your heart rate, raises blood pressure, and stimulates brain activity. If you are addicted to nicotine, withdrawal symptoms may wake you at night. It also goes without saying that quitting smoking offers other health benefits.

Your bed

* Should be used only for sleeping, reading and sex!
* No working in bed;
* No watching television;
* No playing computer games.

* Should be comfortable. This may sounds obvious, but if your bed is too hard, or too soft, you will not sleep well. If you have not bought a new mattress in the past 10 years, consider whether or not it is time for a new one. If you have joint pain or get cold at night, use a mattress pad or underlay. If you get cold at night, use a duvet with a high tog rating rather than layers of blankets that can be heavy. If you get hot in the middle of the night, try using two thinner duvets so you can throw one off in the middle of the night. If you share a bed, and you both have disrupted sleep, trying using separate sets of sheets and duvets, so you are not competing with your partner for your bed coverings.

Your bedroom

Should be:

* Cool (18-20 C) but not cold;
* Well-ventilated;
* As dark as possible;
* As quiet as possible.

Your bedroom should not have a television set or a computer in it. If it does, make sure they are switched off at the wall (so there is no light showing.) Your mobile telephone must be switched off and left in another room before you go to bed.

Getting ready for bed

* Establish a pre-sleep ritual. For example: switch off your mobile phone, have a snack, put the cat out, clean your teeth, get into bed, read a book for a few minutes. Or: walk the dog, switch off your mobile phone, have a bath, clean your teeth, get into bed, read a book for a few minutes.
* Worrying
* Don't take your worries to bed. Try not to think about your job, school, daily life or illness when you are in bed. If you are naturally a worrier, try 'active worrying' whereby you use a worry period during the late afternoon or early evening. Write a list of the things that are worrying you, and decide which ones you can do something about the next day. Decide on a plan of action for those. Leave the others on the list for another day.
* Don't worry about not sleeping. Humans have amazing capacity to do without sleep, and a good night's sleep is often enough to restore the balance. Contrary to popular belief, insomnia is not lethal. It might make you grumpy, and in the long term it can be deleterious to your health, but it will not kill you. It is not clear how much sleep is essential to life, but it is much less than the average insomniac gets, so worrying about not getting to sleep is counter-productive.
* Remember if you can't sleep, you can always rest. One of the major functions of sleep is to allow your body to rest. While you are asleep, your heart slows down significantly. The simple act of lying quietly in bed achieves a decrease in heart rate. So, even if you spend 8 hours in bed, resting without sleeping, this is better for you than being up, pacing about and being anxious about not being able to sleep.

Falling asleep & staying asleep

Get into your favorite sleeping position. If you don't fall asleep within 15-30 minutes, try getting up, going into another room, and reading until you are sleepy. Some people find that listening to the radio or a talking book helps them go to sleep. Radio is a much less stimulating medium than TV, so listening to the radio is fine.

Getting up in the middle of the night

Most people wake up one or two times a night for various reasons. If you wake up and cannot get back to sleep within 15-20 minutes, you do not need to stay in bed trying to sleep. Get out of bed if you want to, but if you get up, you should leave the bedroom. You can sit quietly, read, listening to the radio, have a drink or a light snack, do a quiet activity such as a crossword puzzle, or take a bath.

* Do not do office work;
* Do not do housework;
* Do not watch television;
* Do not play computer games;
* Do not check your e-mail;
* Do not check your phone messages.

After 20 minutes or so, go back to bed.

Remember that your sleeping time starts at your chosen bedtime. If you don't sleep, you shouldn't roll your wake-up time forward to compensate. You should get up 8 hours after you went to bed.

Is a new technique set to revolutionize Huntington's disease genetic testing?

feedback@hdbuzz.net (Dr Tamara Maiuri) — Mon, 18 Mar 2013 07:11:32 +0000

Genetic testing offers at-risk people the option of knowing for sure whether they carry the gene that causes Huntington's disease. For a tiny minority of people, the basic test needs to be followed up with more detailed analysis before a result can be given. Now a new technique may bring quicker results for those people. The new method is a small but important improvement that doesn't change any existing test results.

The Huntington's disease gene, twenty years on

2013 is the twentieth anniversary of the identification of the gene that causes Huntington's disease. This discovery in 1993 paved the way for our current - and ever-growing - knowledge of the gene's harmful effects in the brain, and how we might target them for therapy.

It also meant that people could undergo genetic testing to see whether they carry the disease-causing gene.

What exactly is a disease-causing gene? Each of us carries the huntingtin gene - in fact we carry two copies of it: one from mom, and one from dad. The huntingtin gene has a section that varies naturally from person to person - a region made up of repeating 'CAG' triplets. (C, A, G and T are letters used to represent the four chemical building blocks strung together to form the DNA from which genes are made).

Most people have about 15-25 CAG repeats in each copy of the gene. However, if a person has a huntingtin gene with more than 39 repeats, they will develop Huntington's disease at some point in their life. That's because large CAG repeats tell our cells to make a version of the huntingtin protein that's harmful. It's possible to find out exactly how many repeats an individual has in each of their huntingtin genes - and this is the basis for genetic testing.

When a person with no symptoms of Huntington's disease has a genetic test to find out whether they will develop HD in the future, it's called predictive testing. When someone with symptoms suggestive of HD has a genetic test, it's known as diagnostic testing. But the test itself is the same - counting the CAG repeats.

A new, improved genetic test?

Several recent news stories have reported the development of a new genetic test to determine the number of CAG repeats in a person's huntingtin genes, boasting improved accuracy and shorter turn-around time. The scientific work behind the reports was led by Dr Elaine Lyon of the University of Utah and published in the Journal of Molecular Diagnostics. So what does this mean for people who have already been tested? And for those who are considering testing?

We'll come on to the new testing technique in a moment. First, let's look at how the currently used test works and how accurate it is. How do labs determine the number of repeats in an individual's genes?

How the test works now

The DNA needed for the test comes from a patient's blood sample. Once the DNA is purified, a technique called the polymerase chain reaction, or PCR, is used to zero in on the two huntingtin genes and whip off millions of exact copies for further analysis. These little pieces of DNA are then sorted by size, to determine the number of CAG repeats in each gene: the more repeats a gene has, the larger the "PCR product" will be.

For the vast majority of patient samples, the test ends at this point because this technique is very reliable and accurate.

A handful of troublemakers

There are a few people, however, whose genes don't cooperate with the standard PCR technique used for genetic testing. For example, if one of the CAG repeats is very large (more than about 150 repeats), it can be too big for the standard PCR method to detect it, so it can appear like there is only one, normal-sized gene. This exact same picture occurs when both copies of a person's HD gene have the same number of repeats, say 15 in one copy and 15 in the other.

This situation, while rare, is confusing, because it means the PCR test occasionally can't tell us whether a person has two normal repeats of the same length, or has one normal and one very large repeat - clearly an important difference.

The same thing can happen if a person carries a small, rare variation or 'spelling mistake' in the sequence where the PCR process 'zeros in'. In cases where a small spelling mistake prevents the PCR process from working, one copy of the gene goes undetected and again, it ends up looking like the patient carries two identical copies with equal CAG repeat lengths.

Geneticists are crafty!

For someone to inherit two copies of the huntingtin gene with the exact same repeat length is rare, and since the lab folks doing the test are aware of its technical limitations, this situation raises a red flag. Thankfully, because geneticists are cunning people, we already have a good way of getting round it. Samples with this type of result are analyzed further, to be absolutely sure of the result.

The current protocol for double-checking a suspect sample is an additional PCR-based test involving a region next to the CAG repeats. If this step distinguishes the two genes, then further testing is not necessary. However, if the sample still appears to have two identical copies, a procedure called Southern Blotting is used to make sure an expanded CAG region wasn't overlooked. The downside is that Southern blotting is relatively expensive, requires a large blood sample, and has a long turn-around time.

Enter the new technique

This second-stage analysis is where the new test comes in.

The newly developed test makes clever use of PCR for the double-checking step. What's clever about it is that instead of zeroing in on just the region around the CAG expansion, this method also zeros in on the CAGs themselves. The result is that, instead of one bit of DNA being copied many times, lots of different-sized copies are produced.

When separated by size, these form a "stuttering" pattern instead of one exact, full-length product. But the biggest CAG-lengths seen in this pattern reflect the true length of the person's gene.

This is helpful in those cases where the expansion is very large, because the technique doesn't fail with big CAG repeats, as it can with the standard PCR method. If a stuttering pattern appears, it means that there is an expanded gene. If not, then the person truly has two copies with the same number of CAGs.

So let's answer some of those questions

So does the new test have improved accuracy and turn around time? Yes and no! It's certainly superior to Southern blotting for the small proportion of samples requiring additional analysis. But the vast majority of people can still be easily and accurately diagnosed using standard methods.

Do people who have been tested in the past need to be re-tested? Certainly not. Existing results are still accurate. Even people who previously needed a two-step test to get a result, including a second PCR step or a Southern blotting test, can rely on the result of that process.

Will the new method be implemented in genetic testing in the future? Probably, but there's no hurry and it may not be adopted everywhere. It is likely to be adopted by some diagnostic labs, and in fact some already use similar clever PCR tricks.

The truth is that this new test is really just a small incremental step in the genetic testing story. In fact it has its own limitations - for genes carrying repeats larger than about 150 CAGs, the Southern blot technique will still be necessary.

And although it is designed to zero in on a region with no known variability (to avoid overlooking a gene with a rare spelling mistake), this is not to say that new spelling mistakes won't turn up in a few individuals that could confuse the new technique.

So, whatever you may have read, Huntington's disease genetic testing has not been revolutionized by a new test. We do, however, now have a useful new weapon in the armory that will help everyone who wants one to get a rapid, reliable result.

HDBuzz thanks Dr Mary Sweeney of the Neurogenetics Laboratory, National Hospital for Neurology & Neurosurgery, London, UK for her input in preparing this article.

No surprises in published results from HART study of Huntexil for Huntington's disease

feedback@hdbuzz.net (Dr Ed Wild) — Tue, 12 Mar 2013 10:02:40 +0000

A new paper in the journal Movement Disorders reports the findings of the HART study of pridopidine, also known as Huntexil - a new drug aimed at improving movements in people with Huntington's disease. Unfortunately this publication doesn't change much - a new, larger trial is still needed before we will know whether Huntexil works.

Pridopidine, aka Huntexil

Huntexil is an experimental drug which it's hoped may be beneficial for improving the movement problems experienced by people with Huntington's disease. It is thought to act by stabilising the behavior of the brain transmitter dopamine. Also known by its chemical name pridopidine, Huntexil was developed by the Danish company NeuroSearch and acquired by Israeli drug giant Teva in 2012. Announced shortly after Dr Michael Hayden took over as Chief Scientific Officer in 2012, the acquisition of Huntexil represented a new commitment to HD research by Teva.

HART

The HART trial precedes Teva's involvement, and was one of two large trials conducted by NeuroSearch before they sold the drug. HART involved 227 volunteers with Huntington's disease and was conducted in the USA between 2008 and 2010. The results of the study are fairly well-known since they've been announced at various scientific conferences and in press releases, and we've written about them here at HDBuzz, too.

The reason Huntexil has raised its head now is that the findings have just been published in the scientific journal Movement Disorders, after a fairly lengthy three-year delay.

Volunteers were given one of three different doses of Huntexil, or a dummy 'placebo' tablet, for three months. The drug was safe and well-tolerated, though one patient on a medium dose experienced seizures.

The results were analysed according to a plan that had been set out in advance. That's important to avoid the pitfall of 'fishing' for positive results and only presenting those that happen to be favourable. According to the pre-specified analysis, Huntexil didn't improve volunteers' movements at any dose. It came close on a couple of 'secondary' measures, but essentially the trial was negative.

The broader context

While it's good that the data from HART are now published, this new paper doesn't contain any surprises, and it doesn't change what needs to happen next for Huntexil to get licensed.

HART is one of two large studies of Huntexil carried out by NeuroSearch. Results of the larger study, MermaiHD, were published in 2011 and again, the drug failed to meet the pre-specified level of success to declare the result positive.

When the pooled results of both trials were presented to the European and American regulators, the EMA and the FDA, NeuroSearch was told that it would need to run a third large trial that met the pre-specified tests for success, in order to get a license for the drug. One question was whether the trials had used high enough doses of Huntexil to get the biggest effect.

Teva has announced its intention to "design and complete new clinical studies of Huntexil", so we can hopefully look forward to an announcement of such a trial in the near future.

Liver changes in Huntington's disease patients suggest more 'whole body' research needed

feedback@hdbuzz.net (Dr Jeff Carroll) — Wed, 6 Mar 2013 10:12:10 +0000

Huntington's disease patients seem to have a lot of changes outside the brain, but these issues haven't yet been studied in great detail. New evidence reveals that Huntington's Disease mutation carriers have differences in liver function, even before they have symptoms of HD. This new finding might help us understand the metabolic changes experienced by HD patients, which are currently poorly understood and under-studied.

HD is a brain disease, right?

Huntington's disease is often described as a 'neurodegenerative' disease. This just means that the main symptoms of the disease are thought to be caused by the early death of special brain cells called 'neurons'.

Many of the most prominent symptoms of HD are almost certainly caused by the early death of neurons, including the noticeable movement symptoms that patients experience. It's also likely that the problems with thinking and emotional regulation that make HD so difficult are also due to dead or dysfunctional brain cells.

Surprisingly, the mutant gene that causes HD is active, or transcribed, nearly everywhere in the body. When scientists first discovered the gene, they initially thought that it might only be made in vulnerable parts of the brain. In fact, it turned out that while only certain brain cells die during the course of HD, almost every cell in the body actively makes the HD gene.

In light of this widespread activity of the HD gene, it be surprising that scientists are really only just beginning to appreciate that things go wrong in HD patients outside the brain.

Some of these changes outside the brain are important for understanding the disease. At HDBuzz we've previously covered changes in the immune system of HD patients, while 'calming down' the immune system in HD mice makes them better, even when using drugs that don't get to the brain!

Other aspects of Huntington's disease are less well studied, but might be really important. Many HD patients lose weight, for example, even though they are eating sufficient calories. An early study of lifestyle factors suggested that HD patients who weighed more when they were first diagnosed with HD had a slower course of disease.

'Metabolism' is the term scientists use to describe all the chemical processes that enable our bodies to turn food into energy. Changes in metabolism leading to weight loss could have their origin in many different parts of the body - for example, the muscle, fat or liver. We've only just begun looking for changes in these other organs in Huntington's disease patients.

Is the liver working less well in HD?

Many years ago, when physicians were first examining the organs of people who had died of Huntington's disease, they noted that the livers seemed to be somewhat shrunken. Unlike brain cells, cells in the liver regenerate when they're damaged. Cells in the liver of HD patients appear to be removed and replaced more quickly than in people without HD, which might mean that they're experiencing more damage than normal.

Based in part on these observations, scientists have examined changes in the liver of mouse models of HD. Prof Jenny Morton, of the University of Cambridge, is particularly interested in changes in sleep in HD. As part of her studies in sleep, she's studied which genes are turned off and on in the liver of HD mice over the course of a day. Mice, like humans, turn on different genes at different times of the day.

This complex regulation of turning specific genes on and off in the liver throughout the day doesn't work right in HD mice. This could have major consequences for the metabolism of the whole body, because the liver plays a key role in metabolism.

Heavy, man

But are there changes in the liver in human Huntington's disease patients? New evidence from a team of researchers led by Drs Carsten Saft and Sven Stüwe, in Bochum, Germany, suggests that there are.

The team did a very simple test of liver function in three groups of people: control subjects, people with the Huntington's disease mutation but no symptoms of disease, and HD patients with symptoms. Each person drank a small amount of water that contained a chemical called methionine.

Methionine is one of the 21 'amino acid' building blocks that our cells use to make all the proteins they need. So methionine naturally occurs in large amounts in the body.

The methionine provided by researchers was subtly different - they used methionine that had a abnormally heavy carbon atom. This gives each methionine molecule a different weight than normal, which lets the scientists use special equipment to track the heavy carbon drunk by the study subjects.

Why would they want to do this? It turns out that methionine that we drink or eat is only broken down in the liver, and the progress of this breakdown can be followed by looking for heavy carbon atoms in the carbon dioxide that patients exhale.

The test is very simple and pretty cool. Volunteers downed their amino acid drink, and exhaled into a machine capable of determining how much heavy carbon they were breathing out. But the implications are very important - many years of evidence suggest that we can accurately measure healthy liver function using this test.

HD patients exhaled less labeled carbon than control subjects did - a finding that suggests altered liver function. People carrying the HD mutation, but without symptoms of HD, also had less of the heavy carbon in their breath.

What does this mean?

This is the best evidence we yet have that liver function is altered in Huntington's disease patients and people carrying the mutation. We also know that normal liver function is very important for regulating the metabolism of the entire body.

It's important to note that these changes are subtle, and they don't mean that people with the HD mutation have 'liver disease' or 'liver failure' - and there's nothing to suggest that they are at increased risk of developing liver problems that could be risky in their own right.

We're still a long way from understanding how liver changes might contribute to the changes we see in the metabolism of HD patients, but at least we now have a target to study. This finding is sure to give confidence to researchers interested in studying these types of changes, so look for more exciting 'whole-body' research in the future.

The 'N17' region of huntingtin protein: an address label in Huntington's disease?

feedback@hdbuzz.net (Joseph Ochaba) — Tue, 26 Feb 2013 17:50:07 +0000

New research is helping understand how the mutant huntingtin protein moves around the cell. Discovering where huntingtin ends up, and why, could help us understand HD. Now, Canadian researchers have shown that a small piece of the huntingtin protein behaves like an 'address label' for the whole protein. By studying this label and how it affects Huntington's disease symptoms, we may be able to better understand what goes wrong in HD and hopefully generate a disease-modifying therapy.

Big things can come from little packages

We know that all problems in Huntington's disease are due to a mutation or error in the genetic blueprints for making a protein called huntingtin. In those diagnosed or destined to develop the HD, this 'spelling mistake' at the beginning of the genetic instructions, causes a particular bit of the protein to be longer than normal. But the functions of the normal protein, and the ways in which the mutant protein causes damage, are still rather mysterious.

When a protein is being made, little building blocks are string together like beads on a string. In someone with the Huntington's disease mutation, too many building blocks called 'glutamine' are added at the beginning of the huntingtin protein.

Scientists call this bit of huntingtin containing the extra glutamines, the N-terminal region. Soon after the Huntington's disease gene was discovered in 1993, scientists determined that the N-terminal region is the most harmful bit of the huntingtin protein.

Over the past decade, researchers have identified a critical role for an even smaller piece of huntingtin, the first seventeen building blocks known as the N17 region. This region seems important in telling huntingtin where to go and what to interact with.

Studying these features of huntingtin is important because once we understand how the N17 region works, we might be able to develop drugs to alter its behavior and make it less toxic to our precious neurons.

Location, Location, Location!

Recent publications by Prof Ray Truant from McMaster University in Canada, and Marc Diamond of Washington University in St Louis, USA, have examined this particular piece of the huntingtin protein and its potential impact on the disease.

The scientists revealed that the N17 piece of huntingtin appears to function as an 'address label' to tell the cell where the huntingtin protein should be delivered.

Where exactly Huntingtin's final destination in the cell is, plays an important role in the progression of Huntington's disease. Huntingtin does different things in different places. In some locations, it may be less dangerous than in others. Exactly where huntingtin is found inside cells can have a major impact on the its normal activities and whether or not the cells can deal with the mutant protein.

Previous studies told us that huntingtin can shuttle between various regions of a cell by means of its 'address label'.

An address for huntingtin

The new research from these two groups has gone into greater depth to determine that the N17 piece of huntingtin resembles something called a nuclear export signal.

A nuclear export signal is a bit of a protein which acts like an 'address label' to tell the cell where to deliver a package - in this case the huntingtin protein. The nuclear export signal tells the cell to keep the protein out of the nucleus, where the all-important DNA is kept. Instead, a protein with a nuclear export signal ends up in the cytoplasm, the squishy bit of the cell that surrounds, cushions, and protects all the internal machinery of the cell.

If you think of the cell as a city, the nuclear export signal keeps the package out of the city hall, instead allowing it to float around the open spaces of the city like its public parks.

That's the story for normal huntingtin protein. What about the mutant protein?

Well, in Huntington's disease, there appears to be an error in the 'address label', causing it to be read incorrectly. In this case, the mutant form of huntingtin does not get shuttled out into the cytoplasm - the public park - but instead remains in the nucleus - the city hall.

This error - allowing the 'unauthorized' protein to remain in the nucleus, may contribute to the death of neurons and disease progression. The nucleus is a really important part of the cell - it acts as the a control center of the cell and houses the genetic material.

Lots of research suggests that huntingtin is more toxic to cells when it is in the nucleus. But it can also do harm when it is outside the nucleus, so finding out where and how this package is delivered is important.

How do researchers study something so small?

In order to study how huntingtin is moved throughout the cell, researchers used living cells, grown in small dishes in the lab. They altered the cells genetically so that they only produced the N17 piece of huntingtin. This fragment was joined onto a protein from jellyfish that glows yellow under a microscope.

The attached glowing protein allows scientists to watch the N17 piece as it moves around inside cells. Importantly, it allows researchers to observe where it's delivered if they make changes or introduce deliberate errors into the 'address label'.

Who is delivering these packages?

Based on what they knew already from other proteins with nuclear localization signals, the researchers thought that this label on huntingtin may be recognized by a 'mailman' protein called CRM1. By studying both proteins at once - the CRM1 mailman and the huntingtin package - they discovered that CRM1 interacts with N17's address label based on its unique structure and shape.

Through making small changes to the address label, they found that the nuclear localization signal is very precise. It has to have all of the correct information, shape and other properties, in order to be delivered to the correct location in the cell. If for some reason the label is different from normal, the package is delivered to the wrong location. This seems to be what's happening in Huntington's disease.

Oh Cilia...

Truant and his team demonstrated that the N17 region also controls whether huntingtin ends up attached to the cell's cilia - tiny hair-like propellers on the outside of the cell.

Depending on what's happening to a cell, a protein's address label can be altered using little chemical tags that get attached or removed. The cell's transport machinery can then read these tags like a bar code to determine what to do with huntingtin.

The researchers found that when the N17 bit of huntingtin did not have a tag, it remained inside the cilia. When they put a tag on huntingtin, they found that instead, it built up at the base of the cilia.

What's next?

This new research looks at very tiny events to help us understand an important bigger picture. Research like this helps us understand the signals that move the mutant huntingtin protein around the cell and how this process may be going wrong in HD.

Work carried out in cells like this is a long way from generating treatments that can be used in patients. However, these studies help clarify prior research by different groups with sometimes confusing findings regarding the N17 region of huntingtin.

These results are an important step forward that help us understand how cell damage occurs in Huntington's disease. They opens a new door for researchers to work on future treatments to try to restore the normal shuttling of huntingtin protein.

Though these seventeen building blocks are just a small portion of the whole huntingtin protein, they can have a huge impact on its location and function - and our understanding of Huntington's disease.

HDBuzz Special Feature: Huntington's disease and sleep

feedback@hdbuzz.net (Prof Jenny Morton) — Wed, 6 Feb 2013 20:06:02 +0000

Many Huntington's disease patients have problems with sleep and in the control of daily or 'circadian' rhythms. These problems may actually be part of the range of symptoms in HD, and managing or treating them directly may be beneficial. In this special HDBuzz feature, sleep expert Prof Jenny Morton looks at the science behind sleep problems and solutions in Huntington's disease. Coming soon, part 2: Prof Morton's 'Simple Rules for a Good Night's Sleep'.

After a long day, many of us look forward to the bliss that comes with a good night's sleep. But not everyone who is tired is guaranteed a peaceful night's sleep. For those to whom sleep does not come, the night can seem a lonely and sometimes anguished exile. And more often than not, those who live with the sleepless share the burden. Unfortunately for the person with a neurological disease like Huntington's, the consequences of sleep disturbance may not only be distressing and disruptive, but may also contribute significantly to their symptoms.

We all need sleep

There is no doubt that sleep is an essential and beneficial part of a daily pattern of life. Short-term sleep deprivation causes no lasting damage, but unquestionably impacts mood. Without adequate sleep, people become irritable and unable to sustain attention. They also become unreasonable and short-tempered.

Most people can bounce back after a couple of good night's sleep. But what if you have Huntington's disease?

Evidence is emerging that HD patients frequently suffer from abnormalities in both sleep and in the control of daily or 'circadian' rhythms. It is possible that sleep and circadian dysfunction may actually be part of the range of symptoms in HD. If this is the case, it is important that it is recognized, because sleep and circadian disturbances have negative impact on people's daily lives, even in people without a neurological problem. So, sleep and circadian disturbance in HD patients are likely to contribute to HD symptoms that are worsened by sleep deprivation, such as irritability and anxiety.

Chances are, if you have Huntington's disease and sleep poorly, it will not be solely due to your disease. A significant percentage of the general population suffers sleep disruption due to personal habits, lifestyle or environment. We stay up too late - we get up too early. We take drugs that interfere with sleep, we over-stimulate ourselves with late-night activities such as work or television. HD patients are no exception to this. The difference is that HD patients may not have the reserves that allow a neurologically healthy person to cope with sleep deprivation.

Chronic sleep deprivation is damaging to health in normal people, so it's possible that chronic sleep-wake deficits could actually contribute to mental decline in HD. If this is the case, then treating sleep deficits might delay cognitive and emotional decline in HD.

Is there a difference between sleep and circadian rhythms?

Circadian rhythms and sleep are two different processes, although the terms are often used interchangeably. Circadian rhythms are biological processes that change roughly every 24 hours. They are orchestrated by a small part of the brain known as the suprachiasmatic nucleus or SCN. The SCN is known as the body's 'master clock'. It regulates all your daily activities, including when you wake up and when you want to go to bed.

Sleep is a very obvious 'circadian behavior', because the onset of sleep typically happens once a day. But it is just one of many circadian behaviors that are controlled by the master clock. Others include heart rate, hormone secretion, blood pressure and body temperature.

So, sleep is a circadian behavior that is influenced by the SCN, but it is not generated there. Sleep is a very complex thing, and the process of going to sleep, maintaining sleep and waking up are all controlled by different parts of the brain.

There are multiple stages of sleep that can be identified by looking at the brain's electrical activity. The mechanisms that generate sleep and control movement between these different sleep stages are not fully understood. It is not even known why we sleep, although there is growing evidence that sleep is important for learning and forming lasting memories. We may even do some 'brain housework' while we sleep - by reviewing experiences that have occurred during the day.

Neurological disease causes sleep problems

Sleep abnormalities and disorders of circadian rhythm are already recognized as symptoms in a number of other neurodegenerative diseases, particularly Parkinson's disease and Alzheimer's disease. In fact, sleep disruption in Alzheimer's patients is reportedly the main reason for their institutionalization. This is probably because when an Alzheimer's patient has disrupted sleep, this becomes a problem not only for the patient, but also for their carer.

More research is needed before we will know if sleep or circadian rhythm disruption is part of the complex repertoire of Huntington's disease symptoms, or if it is just a 'knock-on' effect of having HD. But whatever the cause, we should recognize that even mild sleep abnormalities could worsen neurological symptoms in HD patients. Knock-on effects of sleep abnormalities in HD may be critical for determining the care-plan of patients. And, if they worsen thinking and mood disturbances, they may also end up having a have greater impact on quality of life than other symptoms like involuntary movements.

Circadian abnormalities in Huntington's disease

The first clue that sleep or circadian rhythms might be abnormal in HD patients came from a study showing subtle changes in circadian activity profiles, measured by wrist-mounted movement monitors.

Circadian rhythms are difficult to measure accurately in humans, because the rhythm can be masked by other activities such as work and social life. But they are easy to measure in mice, and direct measurement of circadian rhythms in one HD mouse model showed clear abnormalities in circadian behavior.

These mice showed a progressive disintegration of the normal rhythm of rest and activity. That disturbance was mirrored in the HD patients wearing the activity monitors. In the HD mice, there was also disruption in activity levels of genes that controlled the circadian clock in the SCN. These circadian abnormalities in HD mice have now been confirmed by three different laboratories.

Importantly, the breakdown in circadian rhythms in the mice were linked to their decline in thinking function - and restoring good circadian rhythms delayed the thinking decline.

This suggests that some of the thinking problems in the mice were caused by the disruption of sleep and circadian rhythm. If the same thing happens in humans, then improving sleep and circadian function might have a beneficial effect on cognitive and emotional problems in people with Huntington's disease.

What causes sleep disturbance in Huntington's disease?

The most common causes of sleep disturbance in healthy people are depression, stimulant drugs like caffeine and nicotine, and disruptive lifestyles like going to bed late, getting up late and taking naps during the day. So, it is likely that these same culprits are responsible for some sleep disturbance in Huntington's disease patients.

But it's also possible that sleep and circadian abnormalities are direct symptoms of HD, in the same way that chorea is a symptom. There is evidence for sleep disturbance in early symptomatic HD patients who are not taking any medication and not depressed.

So, we don't know yet if there are sleep and circadian abnormalities that are caused directly by the HD mutation, or if it is simply that some patients have disrupted sleep and circadian behavior because they have symptoms of HD.

More research is needed to address this question. But it is interesting that many of the subtle symptoms of early HD are similar to those experienced by normal individuals after sleep deprivation.

Can we treat sleep or circadian disturbances in HD?

If you have Huntington's disease, you don't want to add the consequences of sleep deprivation to your symptomatic burden. But there is good news: there are already well-established treatments for sleep disturbance.

If disrupted sleep is interfering with your daily life, you should talk to your doctor. He or she may be able to prescribe a drug treatment that will help you. This does not have to be a long-term treatment - sometimes a short period of treatment is enough to help you re-establish good sleeping patterns.

If you think you might be depressed, you should also talk to your doctor about depression and sleep problems. Depression is the enemy of sleep, but effective treatments are available.

Remember, too, that many medications that can cause sleeplessness as a side effect. Ask your doctor or pharmacist if the medication you are taking can lead to sleeplessness. Don't stop taking the medication, even if you think it might be interfering with your sleep. Always seek the advice of your physician and other healthcare professionals before changing your medications.

Simple Rules For a Good Night's Sleep

As well as drug treatments, there are recognized, scientifically sound self-help strategies for improving sleep. Whether you are a carer or a patient, improving your sleep hygiene can only be beneficial.

Prof Morton's 'Simple Rules For a Good Night's Sleep', were recently published in the journal Experimental Neurology. In the next installment of this special feature on sleep in Huntington's disease, we'll bring you her 'Simple Rules' in full.

The University of New Orleans has NOT discovered a cure for Huntington's disease

feedback@hdbuzz.net (Dr Ed Wild) — Mon, 28 Jan 2013 16:46:53 +0000

A recent press release from the University of New Orleans (UNO) claims its researchers have discovered a "way to delay symptoms of deadly Huntington's disease". Music to the ears of HD family members everywhere. But does the science live up to the hype? The short answer, sadly, is no.

The science

The science behind the press release focuses on the protein Rhes. The last two letters of its name stand for 'Enriched in the Striatum', because the part of the brain where most Rhes is found is called the striatum.

As it happens, the striatum is also where neurons die early in Huntington's disease. For that reason, and because it's involved in telling cells what proteins to get rid of, Rhes has attracted interest among researchers trying to understand HD and develop treatments.

Some previous research has suggested that the Rhes protein might be an 'accomplice' to the mutant Huntingtin protein in harming neurons. The picture wasn't clear, though, since others have found that it might have some protective effects. So Rhes remains a bit of a puzzle.

Led by Dr Gerald LaHoste, researchers at UNO produced some special mice through genetic engineering and cross-breeding. They wanted to see whether mice that make the harmful mutant huntingtin protein did better or worse, if they also make less than the normal amount of Rhes.

The Rhes-deficient 'HD mice' were successfully bred and observed for six months through a series of tests. The Rhes-deficient mice still got sick and developed movement problems, but did so more slowly than the 'HD mice' that produced a normal quantity of Rhes. The difference represented about two months' worth of decline.

This improvement in the movement symptoms of the mice is encouraging, but wasn't the whole story. Like HD patients, the brains of these 'HD mice' shrink. It turns out that making mice Rhes-deficient, by itself, also caused brain shrinkage. Obviously, brain shrinkage is not something we look for as a side effect in a therapy for HD.

This might be an encouraging start to a long journey, but the amount of work in getting from a genetic manipulation experiment like this to a drug to help human patients is huge, and will take many years, with the potential for failure at each stage, especially when making the leap from mice to humans.

There are many reasons why results in animals often don't translate to patients. Here, it's worth noting that the mice in this work produce only a small fragment of the huntingtin protein, which makes them a less accurate model of human HD than some other mice that could have been used. And the reported 16% delay in symptoms, while better than nothing, is certainly not the biggest improvement that's been seen with a genetic manipulation.

The press release

Press releases are a two-edged sword. They are a useful way of getting the word out about research breakthroughs. But too often, they're written in ways that grab attention but over-hype the published scientific findings.

To put it politely, we have major reservations about the press release that UNO chose to put out to announce this work. It contains a number of claims that could raise people's hopes up for future progress that's very unlikely to be delivered.

There may be many reasons for this, and to be clear, we're not saying anybody has deliberately set out to mislead. But 'overselling' is something that scientists and Universities need to guard against.

"Delaying symptoms of HD"

Starting at the top, the headline claims the researchers have discovered a "Way to Delay Symptoms of Deadly Huntington's Disease".

As we now know, what they've actually discovered is an artificial genetic manipulation that makes mice less susceptible to the effects of the HD mutation, but also have shrunken brains. While it's true that the symptoms were delayed, mice don't get Huntington's disease. All researchers know this, so anyone publishing press releases in the HD field needs to avoid making headlines that could be mistaken for the 'cure' announcement we all wake up hoping to read.

Does a bit of creative headline-writing really matter? Yes - and here's why.

To get new HD drugs to patients, we need drug trials, which generally require hundreds of patient volunteers, drawn from a population of busy people struggling to live normal lives. Huntington's disease is quite rare, and currently only around 20% of people at risk of HD choose to be tested. So the pool of volunteers physically helping us to develop drugs is pretty small, and we rely on people's good will and faith in the scientific establishment.

Whenever someone reads a headline touting good news for HD families, then is disappointed when the science fails to deliver what the headline promised, there's a risk we'll lose a volunteer - pushing the advent of effective treatments a little bit further away. That's an absolute tragedy, and one that's easily avoided by responsible public engagement.

"The first treatment?"

Next, the paper's lead author, Dr LaHoste, says "I believe that these findings are important because they may lead to the development of the first treatment for this horrible disease." But the Rhes pathway is a relative newcomer to the list of targets for Huntington's disease drug development, and the gap between manipulating a target genetically like LaHoste's team did here, and a pill taken by patients, takes many years to bridge.

So LaHoste's statement may well overestimate the potential of this work. But at the same time, it underestimates the progress in developing drugs that's been made by the global HD research community

In fact, experimental treatments like huntingtin gene silencing are so advanced we expect human trials in Huntington's disease patients to begin in the next year or so - treatments with the highest hopes for success we've ever seen.

So, while it's theoretically possible that Rhes-targeted drugs may be the first treatments to slow HD, there are plenty of other approaches that are closer to success.

Why are statins in there?

One statement in the press release is particularly baffling. It reads, "Based on their findings, they believe that a class of cholesterol-lowering drugs, called statins, could greatly slow the symptoms of Huntington's Disease in humans." What's odd here is that neither cholesterol nor statins are mentioned in the actual research paper. What's more, we know of no connection between Rhes and statins.

So this statement appears not to be justified by the scientific work reported, and has the potential to cause great confusion among patients and family members. To be clear, there is no evidence that taking statin drugs is helpful for HD, from any work done in animals, humans or anything else.

Mice are not people!

A little lower down, the press release falls into a common trap. Reporting the delay in symptom onset in the genetically altered mice, it says, "Relative to the lifespan of these mice, the delay translates to about five years in humans."

In our opinion, this is a very unwise thing to suggest. Even LaHoste's original research paper itself cautions that "it is difficult to compare lifespans between species", and anyone who follows HD research knows that, so far, of the many drugs that have benefited HD mouse models, none has produced any benefit in human patients.

Predicting human benefits from mouse work - especially in such specific terms, runs the risk of creating false hope, followed by real disappointment.

What can we learn from this?

All in all, what we have here is a fairly simple study reporting a modest benefit from the genetic manipulation of HD model mice, along with a potentially worrying side effect. It provides some support for the further study of Rhes in Huntington's disease but is a long way from being of direct benefit to HD patients. Work on the Rhes pathway is continuing in several labs and if there's a major breakthrough, we'll let you know.

But the press release that accompanied the paper's publication is a striking example of how - even if nobody involved intends any harm - expectations can be over-inflated by hype, risking harm to our efforts to advance research through the involvement of HD family members.

Above all, we urge scientists and media professionals to exercise caution and responsibility when preparing press releases for the public. The UNO Communications Office didn't respond to our request for comment on this release.

To help yourself sort out the hope from the hype when reading press releases in future, check out our article 'Ten Golden Rules for reading a scientific news story'.

Gone fishing: protein network screen identifies new therapeutic targets in Huntington's disease

feedback@hdbuzz.net (Carly Desmond) — Fri, 18 Jan 2013 02:53:19 +0000

The mutant huntingtin protein doesn't do damage in isolation - all proteins work in connected networks. Researchers at the California Buck Institute for Research on Aging have conducted a large-scale screen to identify protein networks that may be acting to relieve or worsen the harmful effects of the Huntington's disease mutation. Could manipulating these networks offer new therapeutic options for HD?

The Huntingtin Protein: Getting to the Root of the Matter

2013 marks the 20th anniversary of the discovery of the genetic cause of Huntington's disease. For the first time, scientists learned that a repeating DNA sequence in single gene was abnormally long in people who develop HD. Each of our genes provides the instructions our cells need to make a particular protein, which in the case of the HD gene is a protein we call huntingtin. Mutation of this genetic instruction set causes the huntingtin protein to be built with a mistake, leading to subtle changes in the protein's cellular behaviour. As a person with HD ages, these changes have serious consequences, particularly within the neurons of the brain.

This ground-breaking discovery made it a possible for scientists to focus their efforts on a very specific task; in order to truly understand the disease, they would need to learn all they could about the huntingtin protein itself. This means knowing not only what the huntingtin protein does in the body of a healthy individual, but also what is going wrong in the disease.

What could be so important about one protein?

Proteins are often referred to as having specific 'functions' in the cell. To understand what this means, it may be helpful to imagine each cell in our body as a busy factory. It takes a lot of different people doing many different jobs to keep the operations of a factory running smoothly. All of these employees have a specific set of skills, and if any one person fails to do their job properly, the productivity of the whole factory is at risk.

Well, if our cells are like factories, proteins would be the employees. Just like the individual workers, each protein has to do a set of jobs, or 'functions'. When the huntingtin protein is mutated in HD, it affects the way huntingtin does its functions.

Just as no one person could do every job in the factory, no one protein works completely alone. Instead, it exists as part of a network of proteins that interact with each other to work efficiently as a team. So to understand a protein's function, scientists they must also determine what relationship it has to other proteins in the cell.

It has been estimated that our DNA provides the instructions to construct over 30,000 different proteins. Understanding how all of these proteins are connected to each other, and how they might be affected in HD, becomes an almost overwhelming challenge.

Hypothesis and discovery

To help deal with the complexity of modern biology, some researchers have shifted from traditional 'hypothesis-driven' research to an approach called 'discovery-driven' research.

A hypothesis is a prediction that a scientist makes based on what they already know. A good hypothesis is one that can be easily tested. Here is a simple example: say we hypothesize that cats prefer eating chicken over tuna A way of testing this might be to put out two bowls, one containing each choice. By counting the number of different cats that approach each bowl, evidence will be provided to either support or reject the hypothesis.

Hypothesis-driven research works really well, provided you already know a fair amount about the particular thing you are investigating. However, when aiming to figure out what a protein does in a network of thousands of other different proteins, progress can go pretty slow when asking only one question at a time. Imagine you wanted to find out which was the cats' favourite out of 30,000 foods - but could only test them two at a time!

Discovery-driven research is a way to highlight biological processes that might be involved in a disease. You could say this approach generates not answers, but better questions. It tells researchers where to focus their attention for future studies.

Discovery-driven experiments, called screens, involve thousands of different mini-experiments conducted simultaneously.

In some ways, biological screens are a bit like the difference between fishing with a trawling net instead of a rod and line. It's a powerful technique, but requires more effort to sort through what's caught.

Silencing individual genes with RNAi

A new study published in the journal PLOS Genetics, headed by Dr. Robert Hughes of the California Buck Institute for Research on Aging, describes a discovery-driven screen looking for protein networks that are affected by mutant huntingtin. Using a technology called RNAi, Hughes' team worked to identify individual proteins that might be contributing to the harmful effects of the mutant protein.

RNAi stands for RNA interference, and is a form of 'gene silencing'. RNAi is used to reduce the level of a single protein in the cell. This helps to determine what that protein might do and its importance to other cellular activities.

RNAi intercepts the chemical message that's produced when a protein is being made, and destroys it - preventing the protein from being built. Virtually any gene and its corresponding protein can be targeted using RNAi.

An RNAi screen and some toxic fragments

First, Hughes' team grew cells in the lab that had been genetically modified to make them produce the most damaging part of the mutant huntingtin protein. This mutant huntingtin 'fragment' causes the cells to die more quickly if the proper nutrients are not available. The health of the cells can be assessed by measuring changes that occur when a cell is dying.

To identify proteins involved in mutant huntingtin's harmful effects, Dr. Hughes and colleagues used a 'library' of over 7,000 RNAi chemicals, each one targeting a different protein.

Those 7,000 RNAi chemicals were each tested on a separate batch of cells. In this way, the researchers were able to analyze the effects of each protein that was 'switched off'. If silencing a gene makes the cells die more quickly, it suggests that the corresponding protein might normally be protecting the cell. And if the cells die more slowly, it means the protein might be worsening things in HD.

Crunching the numbers

Experiments like this produce a ton of data, so computers used to analyze and make sense of it. Thankfully, many protein networks have already been mapped out using more traditional scientific approaches.

The computer creates a new map, placing the 'hits' from the new data onto the existing network map. Using this technique, Hughes' team found some networks that had more hits than expected, indicating that they might be important to the development of Huntington's disease.

Some of these networks were already known from previous studies, giving the scientists confidence that their discovery-based approach was working. However, they also came across networks that hadn't been implicated in HD before. One network in particular, connected to huntingtin through a protein called RRAS, was highlighted by the screen.

Because of the huge numbers involved, it's important to do separate follow-up experiments to verify the most striking findings. So Hughes' team did experiments in several different cell models, as well as in HD fruit-fly model, and found that RRAS was able to protect against cell death. Even better, they were able to pinpoint specific activities of the proteins within the network that might be easiest to target with drugs.

Knowing our limits

The most exciting aspect of this study is that it highlighted new networks that may be involved in Huntington's disease. However, just as there's no fishing net big enough to trawl the entire ocean, some important protein networks were likely missed with this work.

One reason for this is the cell model used in the screen. Instead of making cells produce the full-length mutant huntingtin gene, the researchers opted to use only a small fragment. That means that any proteins or networks that rely on the full huntingtin protein will have been missed.

Another reason is the cell type used in the experiments. This work was done with commercially-available cells called HEK293. These cells are easy to grow in big batches for large scale experiments like this. But after being altered to have such easy-going properties, they no longer behave the same as a normal, healthy cell in the body - and are certainly very different from neurons.

To make up for these potential weaknesses in the experimental model of the initial screen, all of the RNAi 'hits' were re-tested in cell lines that produce full-length huntingtin, as well as more complex fruit-fly models of the disease. And the RRAS network was examined in an HD mouse model.

What's next?

This work represents a major effort on the part of the researchers involved. Biological screens require a lot of careful planning! However, with this study under their belt, the team could continue this work by performing a similar screen in cells containing full-length huntingtin.

When it comes to the hits of the current screen, there is still so much more to explore. One approach might be to investigate the RRAS network - or even repeat the screen - in more 'accurate' cell models, such as stem cells generated from real HD patients.

Whatever the future of this research holds, this is a good example of how discovery-driven research can generate new targets and ideas, provided we remain aware of the limitations of the techniques. We look forward to learning more about how these new protein networks influence the development of HD, as well as how they might be manipulated in the search for treatments.

Prana Biotech publishes Huntington's disease animal model data for PBT2

feedback@hdbuzz.net (Dr Jeff Carroll) — Mon, 14 Jan 2013 02:02:49 +0000

The Huntington Study Group and Prana Biotechnology are currently running a clinical trial, Reach2HD, to determine whether the drug PBT2 is effective in HD patients. Now, they've released the preclinical data behind the trial, showing the drug is effective in two animal models of HD.

History of PBT2

Many Huntington's disease families have been excited by word of a new player developing a novel treatment for HD. Prana Biotechnology, a drug development company in Australia, has developed a new drug they call PBT2.

HDBuzz has previously written about Prana and their drug, which works in a surprising and novel way. While all the details are not understood, the drug is designed to interfere with interactions between the huntingtin protein and the metal copper.

Interfering with copper in the body may sound like a strange and surprising way to attack Huntington's disease, but there is a history of investigating changes in copper in the brain of HD patients.

Another genetic disease called Wilson's disease is caused by mutations in a gene that helps cells get rid of excess copper. The cells of patients with Wilson's disease accumulate too much copper because they don't know how to get rid of it, thanks to their defective gene.

It turns out that Wilson's disease patients have brain damage in the same areas of the brain as Huntington's disease patients, and that in HD, these parts of the brain accumulate copper too. This supports the idea that copper might be important for the particular parts of the brain that die in HD.

Based on in-house work that suggested PBT2 was effective in Huntington's disease, Prana Biotechnology began working with the Huntington Study Group to initiate a trial of their drug in human HD patients. The trial, currently running in the US and Australia, is called Reach2HD.

This trial happened so fast that few people outside the company had seen the data that suggested their drug was effective. They've now published this data for everyone to see in the new Journal of Huntington's Disease.

The animal models

Before testing a drug in humans, scientists like to have an idea of whether it is safe and effective. The only way to study this is to give the drug to animals who have been genetically modified to carry the same mutant HD gene as human patients.

These animals have problems that mimic, in some ways, those experienced by HD patients. While the animals don't have Huntington's disease, they do provide an objective way of testing whether a drug has an impact on the problems caused by expression of the mutant HD gene.

To test PBT2, the team of scientists, lead by Stephen Massa of the University of California at San Francisco, turned to two different animal models of HD. First, they used a tiny worm with a big name - 'Caenorhabditis elegans'. Unlike humans, with their billions and billions of brain cells, C. Elegans has precisely 302 brain cells.

Forcing C. elegans' worms to express a gene similar to the one that causes Huntington's disease in people causes these worms to become paralyzed and unable to move. Because the worms are so small and have a very short lifespan, they can be used to quickly test whether a drug reduces the harm associated with the mutant gene.

The second animal used to investigate the effectiveness of PBT2B was a mouse that has been genetically engineered to express a mutant HD gene. This gene makes them very sick, very fast - they have problems with coordinating their movements, show shrinkage in the brain similar to that seen in HD patients and ultimately die very young. These mice provide a simple tool for testing a Huntington's disease drug - scientists can simply give the mice a drug and see if it can improve any of their symptoms.

The results

In the worm model, PBT2 was very effective - worms treated with PBT2 were able to live for much longer without becoming paralyzed. Rescuing worms is nice, but it's a long way from people! The mice, despite being small and having fairly simple behaviors, are much closer to people. How did PBT2 do in HD mice?

While alive, HD mice treated with PBT2 showed some improvements in the coordination of their movements - that is, they were slightly less clumsy. More interestingly, treatment with PBT2 prolonged the survival of HD mice by a significant amount: mice treated with the drug lived about 26% longer than untreated mice. That's a pretty decent extension, though we should remember that the mice were still quite sick during the extended period of their life.

Other measures were improved by PBT2 treatment as well. Like many HD patients, these HD mice lose weight. Weight loss can be a major problem for HD patients, and is difficult to combat. Treatment with PBT2 helped HD mice maintain body weight in a fairly dramatic fashion.

In the brain, HD mice showed shrinkage similar to that experienced by HD patients. This loss was significantly, but not completely, rescued by treating the mice with PBT2. This suggests the drug isn't just masking symptoms, but might actually be stopping the brain cell death that causes symptoms to occur.

Caveats and questions

All in all, it's easy to see why these scientists were excited about the results of PBT2. The beneficial effects in the mice, in particular, are pretty impressive.

As with any trial conducted in animals, it's worth thinking about the limitations. The mice, for example, were treated with PBT2 from 3 weeks of age - essentially from when they first start eating and drinking on their own, rather than nursing from their mothers. This is not what will happen in people, who are only being given the drug after their symptoms start. Can PBT2 work, even if it's only given when someone is already sick? We just don't know yet.

PBT2 has advantages over some other experimental drugs in HD. For one, it is known to get into the brain, where it needs to be to work. Furthermore, it has already been shown to be well tolerated in human Alzheimer's Disease patients, making it less likely that the drug will fail because of side-effects.

The clinical trial currently investigating PBT2 in HD patients is formally only designed to study whether the drug is safe in HD patients when administered for 26 weeks. But the investigators are also measuring a host of changes in these patients caused by HD, including behavior changes, thinking problems and biological changes in the blood, urine and brain. Looking at these things now may give us a hint of whether PBT2 is effective.

Especially in light of these positive results in animal models, HDBuzz is encouraged to hear that the trial is now fully recruited, and we look forward to hearing the results.

'Guard dog' proteins reveal surprising connections between Huntington's disease and other brain disorders

feedback@hdbuzz.net (Dr Melissa Christianson) — Thu, 10 Jan 2013 16:30:25 +0000

DNA/RNA-binding proteins, a fancy type of protein that 'guards' the genetic instructions running brain cells, are known to be important in diseases like Alzheimer's and motor neuron disease. New research suggests that these proteins could be key players - and lead to new treatment options - in Huntington's disease as well.

A familiar theme: death by protein

Humans are natural-born recyclers - and not just of the stuff we toss into those eco-friendly bins. We recycle ideas, like remaking Hamlet into The Lion King, or Romeo and Juliet into West Side Story.

Intriguingly, scientists are now discovering that our bodies do exactly the same thing - especially when it comes to brain disease. In recent years, it's become increasingly clear that brain cells have only a few major ways of getting sick and dying - and of responding to being unwell. What's more, it seems these ways are reused and recycled across lots of different brain diseases.

One of the most common ways a neuron can gets sick involves proteins, the molecular machines of the cell. Proteins do everything from handling energy to maintaining a cell's shape. In many brain diseases, proteins break and stop doing their jobs correctly. If the job the protein was doing was an important one - or if the broken protein gets in the way of other proteins trying to do their own jobs - then neurons can get sick and die.

On the surface, the solution to this problem seems clear: fix the broken protein so that it can do its job again. Unless you're working with a condition like Huntington's disease, where the exact genetic cause is known in all cases, that can be surprisingly difficult. The average brain cell has many thousands of different proteins, so identifying the one that needs to be fixed in a specific disease can be a tricky problem.

DNA/RNA-binding proteins: DNA's guard dogs

New research by a group of Canadian scientists trying to figure out what goes wrong in Huntington's disease has highlighted the importance of a special type of protein, called a 'DNA/RNA-binding protein'. What's more, this research has thrown up intriguing new connections between Huntington's and other brain diseases.

Normally, DNA/RNA-binding proteins act like a guard dog, protecting a brain cell's genetic instructions. By joining up with specific genetic messages, DNA/RNA-binding proteins can control which instructions brain cells give to their other protein workers. This means that DNA/RNA-binding proteins are extremely important, because they can easily affect what gets done inside a brain cell.

One important point about DNA/RNA-binding proteins is that they're usually found only in the nucleus (i.e., control room) of a cell, where they have easy access to the genetic instructions they're supposed to guard. However, in HD and other brain diseases, DNA/RNA-binding proteins escape from the confines of the nucleus and run free through the rest of the cell.

We can think of this 'escape' as similar to what happens when your neighbor's guard dog Rex breaks out of his yard: once Rex isn't confined to where he's supposed to be, he runs amok and terrorizes the neighborhood. To return the neighborhood to normal, your neighbor has to catch Rex or prevent him from getting out in the first place.

In exactly the same way, some HD researchers think that preventing DNA/RNA-binding proteins from escaping from the nucleus and running free in the rest of the cell could stop brain cells from dying in HD.

How do you test this idea in a laboratory?

To test this idea, researchers led by Dr J. Alex Parker of the University of Montreal, Qu'ebec, created laboratory animals modeling certain aspects of HD. They genetically engineered worms and mice to give them the extra-long huntingtin gene common to every patient with Huntington's disease. These animals develop cellular and behavioral abnormalities, such as high levels of brain cell death and altered sensitivity to being touched, that the scientists believe imitate aspects of the human disease.

Parker's team then used these animals to ask whether interfering with two specific DNA/RNA-binding proteins could prevent these cellular and behavioral anomalies. The names of these two proteins (TDP43 and FUS) aren't particularly important; what's important is that these proteins are known to escape from the nucleus in human HD.

TDP43 and FUS were partly chosen for this study because they were recently found to be involved in two other brain diseases - frontotemporal dementia and motor neuron disease (also known as Lou Gehrig's disease and ALS).

What did they find?

Starting in the worms, the scientists first interfered with the two DNA/RNA-binding proteins by replacing the normal proteins with different versions that aren't functional. In our guard dog analogy, this would be like replacing Rex with a miniature poodle. Even if the poodle escapes, he probably won't wreak havoc on the neighborhood.

They found that this protein replacement prevented the abnormalities that normally occurred in the HD worms, even though the mutant huntingtin protein was still there. That suggests that some interaction between mutant huntingtin and the normal DNA/RNA-binding proteins is needed for damage to occur.

To provide more evidence that interfering with DNA/RNA-binding proteins could be helpful in HD, the scientists next turned to some HD model mice. In brain cells from these mice, they used a cool technique to get rid of the two DNA/RNA-binding proteins altogether. In a nutshell, the scientists prevented the proteins from being made - which means that they theoretically couldn't be around to do bad things in mouse brain cells.

In our guard dog analogy, this would be equivalent to neutering Rex's father so that Rex could never be born. A dog that doesn't exist can't very well terrorize a neighborhood.

Excitingly, the scientists found that preventing these proteins from being made prevented the mouse brain cells from dying due to their extra-long huntingtin gene.

From these experiments, the researchers concluded that the two DNA/RNA-binding proteins they were studying may be involved in HD. Further, they suggested that interfering with these proteins could provide new therapeutic avenues for HD treatment.

So, what does this mean for HD?

It's exciting news that interfering with two specific DNA/RNA-binding proteins improves models of HD. These findings help us to understand how Huntington's disease leads to brain cell death - which could potentially lead to the development of new therapeutics so urgently needed by the HD community.

And because the two DNA/RNA-binding proteins the scientists studied are also important in frontotemporal dementia and ALS, this research forges a new link between Huntington's disease and these other brain disorders. Even though these other diseases are currently just as incurable as HD, this link means that scientists can recycle some of the research done in the context of other diseases to get a running start on uncovering what goes wrong with these proteins in HD.

And it works both ways - Huntington's disease, where the genetic cause is known, can now be used as a model to study the functioning of these DNA/RNA binding proteins in a way that could help researchers understand other diseases.

Of course, it's important to remember that any early scientific results need to be taken with a grain of salt. First, the researchers here were studying animal models of HD (not people), so there's plenty of work to be done to show that these same proteins are important in humans. Second, even if DNA/RNA-binding proteins do play an important role in human HD, drugs targeting these proteins require a lot of time and resources to develop and are thus still a long way from being viable options in the clinic.

Nevertheless, these findings represent a new line of inquiry - and an exciting opportunity for researchers from different disease areas to help each other - in our efforts to figure out how Huntington's disease damages neurons and identify new therapeutic targets.

Dyeing to prevent dying? Methylene blue beneficial in Huntington's disease mice

feedback@hdbuzz.net (Dr Tamara Maiuri) — Tue, 8 Jan 2013 15:06:57 +0000

One of the hallmarks of Huntington's disease is the formation of protein clumps in brain cells. It's not clear whether these protein bunches cause disease, but treatment with a blue dye that disrupts the clumps has now been shown to delay symptom onset in an HD mouse model. So what's next for this drug that turns patients' eyes and urine blue?

Something old, something blue

Methylene blue is a dye that has many uses. In medicine, it has been used for over 100 years to treat conditions ranging from malaria to urinary tract infections.

One reason it's used to treat so many things might be that it has many biological effects. Methylene blue can act as an anti-oxidant, protecting cells from oxidative damage, and there's some evidence it can help cells clear out old proteins they no longer need. It can also keep proteins from sticking to one another.

According to new research in cells, fruit flies and mice, methylene blue may also have the potential to help prevent damage in Huntington's disease. This study suggests that methylene blue's ability to block protein clumping is important here.

A sticky situation

In order to understand the problem with sticky proteins, let's go back to the basics.

Where do proteins come from? From a nice, juicy steak, right? It's true we get protein from our diet, but our bodies then break the proteins down into tiny building blocks, ready to be assembled into the exact proteins we need.

To decide how to put the building blocks back together to form all the chemical machines they need to function, our cells consult their genes. Genes, which are made up of DNA, act as recipes or sets of instructions.

The gene that causes Huntington's disease is a recipe for a protein called huntingtin. Patients carrying an expanded, or mutated, form of the HD gene produce an expanded, or mutant, huntingtin protein.

We're not fully sure exactly how the expanded huntingtin protein causes harm, but one of its trademark features is that it sticks together, forming clumps of protein in the brain cells of patients. Scientists call the clumps 'aggregates' because it sounds more impressive.

Aggregates of various proteins are found in patients with other diseases like Alzheimer's and Parkinson's. So if mutant huntingtin forms aggregates, and the aggregates are found in neurodegenerative diseases, then the aggregates must cause the disease, right?

Well, if someone told you that fire trucks are always found at fires, you'd be mistaken to conclude that fire trucks cause fires. The truth is that scientists still don't understand whether the aggregates cause the trouble, or whether they are simply generated by dying brain cells.

To complicate matters, there are different types of aggregates. Some are easy to dissolve, while others are hard to dissolve. Evidence is mounting to suggest that it's the unpaired proteins and the smaller, easy-to-dissolve aggregates that really cause the trouble in HD. Those are called soluble aggregates, while the hard-to-dissolve ones are called insoluble aggregates.

Enter methylene blue - a blue dye that can block the formation of both kinds of aggregates.

Divided they fall?

Researchers in California, led by Prof Leslie Thompson, first looked at mutant huntingtin protein isolated in a test tube, tends to form soluble and insoluble aggregates. They found that methylene blue not only blocked the formation of aggregates, but also disrupted already-formed clumps.

This breaking-down of existing aggregates, on top of preventing new aggregate formation, may be good news for patients who already have protein aggregates in their brains.

Proteins in a test tube are one thing, but what about brain cells? The next thing the team did was feed methylene blue to neurons grown in a dish, that had a mutant copy of the HD gene. Methylene blue blocked mutant huntingtin from clumping inside the neurons. The cells also survived better with methylene blue treatment, a good sign.

Moving up a notch, the team asked what would happen if they fed methylene blue to some fruit flies engineered to carry the HD gene. They found that neurodegeneration in the flies wasn't as bad if they fed them methylene blue at an early stage. However, it had no real effect if they introduced it after they reached adulthood.

Next stop, Huntington's disease model mice. The researchers used R6/2 mice, which get sick very quickly. Methylene blue once again stopped the aggregates from forming and delayed the onset of movement problems.

It didn't prevent the symptoms entirely, but follow-up studies in a more slowly-progressive mouse model, that resembles human HD more closely, might give a clearer picture.

At the very least, a drug that disrupts mutant huntingtin aggregates can tell us a lot about the role they play in disease.

What about humans?

The idea to look at methylene blue as a treatment for Huntington's disease didn't come out of the blue. In fact, this curious dye has a... colorful history in the field of neurodegeration and dementia research.

Methylene blue also affects the formation of aggregates in Alzheimer's disease, and a clinical trial held in 2008 took the Alzheimer's research community by surprise when huge improvements were reported in patients who took the drug.

That excitement faded somewhat, since no new data came out after the initial study.

Recently, TauRx Therapeutics Inc. - the company behind the original methylene blue trial - announced the initiation of two global clinical trials with Alzheimer's patients using an 'improved' version of methylene blue. The new version is called LMTXTM. It's touted to have improved ability to reach the brain and fewer side effects. What's less clear is why the company didn't press on with a trial of that drug, when the original trial appeared so successful.

The 'improved' drug is a step in the right direction, since it's unclear whether methylene blue can reach the brain in humans when taken orally.

Methylene blue also has a curious property that makes it uniquely tough to test by clinical trial.

One important aspect of clinical trials is that both researchers and patients should not be biased when recording and reporting symptoms. To avoid bias, trials are double-blinded, which means that neither the researcher nor the subject knows who is taking the actual drug and who is taking the control, or placebo.

But subjects have to take methylene blue until they are blue in the face-literally! Since it's a dye, methylene blue turns the urine and the whites of the eye blue, making it impossible to run a blinded study. In the Alzheimer's trial, blue pee was a sure sign that a patient was taking the real drug. Knowing that they're taking the active treatment can make patients feel better, often quite substantially - the so-called placebo effect. Could that have biased the outcome of the trial?

Clearly, there are challenges to face before we can say that methylene blue will help treat Huntington's disease. This drug has been used safely in humans for a long time, but for human trials in HD to be worthwhile, we'll need to see data proving that the drug gets into the human brain and reaches a level we'd expect to have an effect on aggregate formation.

These preliminary results reported by the Californian research group surely suggest it's a drug worth pursuing to study aggregation and as a possible treatment approach, and the results of the Alzheimer's trial will be of much interest to Huntington's disease patients and families alike.