Huntington’s disease prevention breakthrough? An interview with Professor Lesley Jones

Prof. Lesley JonesTHOUGHT LEADERS SERIES...insight from the world’s leading experts

What is Huntington’s disease?

Huntington’s disease is an inherited disease which, whilst quite rare, is one of the more common inherited neurodegenerative diseases. About 1 in 6,000 people in the UK are at risk and what’s horrible about this disease is that if one of your parents has it, then you have a fifty-fifty chance of inheriting it.

The disease is caused by an expanded section of a particular gene on chromosome 4. It’s a repeated section of the DNA that consists of the letters CAGCAGCAG over and over again. We all have this repeated section in our Huntington gene, but in most people there are 35 repeats or less. In the Huntington’s population, there are 36 CAG repeats or more. If there are more than 40 repeats, the person will definitely get the disease if they live long enough.

We’ve known about this for about twenty years, but, essentially, there has been a huge amount of work done on the biology that might arise from this mutation. Pretty much every area of biology that you might think of has been implicated as being involved in Huntington’s disease. It’s been very difficult to know what you should target in order to treat the disease.

Who does Huntington’s usually affect?

The disease onset itself usually occurs during mid-life, although people can get it when they’re older or younger and sometimes children get it.

One of the main determinants of when people get the disease is the length of the CAG repeat that I talked about. If people have a repeat that’s in the high 30s or low 40s, then the chances are that they will get the disease later, whereas if they have a really long repeat– in the 60s or 70s – then, the chances are they will get the disease in childhood.

However, that’s not an absolute determinant of when people will get the disease. If people have a repeat of 40, for instance, they could get the disease in their 20s or in their 70s. We can’t predict exactly what will happen.

One of the things that we have known for a long time is that part of what might alter the age of disease onset are other genetic factors.

Are environmental factors also at play?

There probably are environmental factors as well. We don’t know what they are either. It’s quite hard to track down environmental factors, particularly in a relatively rare disease where individual people might live in very different environments with respect to all sorts of different aspects of their lives. It’s quite hard to work out what those effects might be.

Why is there currently no treatment that can alter the course of Huntington’s disease?

There is currently no treatment that can alter the course of the disease, however, there are some treatments that can treat specific symptoms. If, for instance, people have psychiatric symptoms such as depression or apathy, which sometimes go with the disease, then those symptoms will get treated in the same way as they would in other people.

There are also some treatments for the movement disorder that is part of this disease, but there is no treatment that actually alters the processes that are killing cells in the brain and therefore nothing to stop the neurodegeneration.

Although some of the symptoms can be treated to help people manage the disease, there’s no way of preventing the inexorable progression of the disease once it’s started.

How much was previously known about the biological mechanisms that underlie Huntington’s disease?

In a way, we almost knew too much because we know that long repeats in the Huntington’s gene affect many cellular systems. They affect transport within cells and the signalling of one cell to the next in the brain and possibly elsewhere as well. They also affects the way cells metabolize energy and how much of each gene product is made in cells.

We’ve known for a long time that the mutation affects all sorts of systems, but it’s hard to know which of those systems are important in allowing the disease itself to be manifest.

Can you please outline your recent study that analysed the age of onset and the DNA of over 6000 people with Huntington’s disease? What were the main aims of this research?

The main aim of this research was to see whether there were variants in the DNA that would highlight genes and molecular pathways that might cause the disease to manifest in people. In other words, not to use models of any sort, but to look at people themselves with the disease to see if we could find out what changed the disease in those people. The study took a long time and was a large international collaboration with groups in the USA, Germany and the UK organising the research and HD subjects from all over the world contributing their DNA.

You can, if you like, think of this as a natural clinical trial. In people who have an older age at disease onset than might be predicted by the length of their CAG repeat, those people could be carrying variants in other parts of the genome that are protecting them from the disease processes. Likewise, people who have an earlier disease onset might have DNA variants in their genome that predispose them to developing the disease earlier.

Critically, those pathways are ones you might be very interested in developing therapies to target because you might be able to prevent early onset and delay it until people are much older and perhaps have died of something else.

What were your key findings?

We were surprised to find that we did get a very clear signal. We found that this highlighted a limited number of pathways in our current study. These would be the pathways that you would think ought to be those that are tackled therapeutically. They may not be easy to tackle therapeutically, but nevertheless we ought to be thinking about how we might go about this.

The key pathways that we seem to be finding are pathways that affect DNA repair, energy metabolism and the oxidative processes that go on in cells. For instance, in lung cancer, one of the lesions that occurs in the DNA occurs because of the oxidative processes caused by cigarette smoke.

Those are the kind of pathways that we ought to be looking at rather than some of the other pathways which have been tackled more recently by people looking at this particular disease.

What impact do you think this research will have on the development of new treatments?

I think it will concentrate people’s minds on these particular areas of biology and that will allow us to progress faster because it gives us a good clue about what’s important in people with the disease. That’s the critical element here.

We have a lot of reagents in Huntington’s disease. We have lots of models and this allows us to go back to those models and look at what are more likely to be the relevant molecular sequelae that we ought to be looking at in order to try and cure the disease. It’s very important that people go back and do this.

Realistically, how long do you think a treatment for Huntington’s disease will take to develop?

I think it will probably be faster because of this finding because it will allow people to be less distracted by other things that may not be relevant and therefore direct our focus.

It is unlikely to happen within the next few years, but it may allow us to repurpose some treatments that are currently used in other disease fields and try out some of those drugs and molecules that may have an effect on the systems that we’re interested in.

While they may not be perfect, they provide a starting point for the pharmaceutical industry, particularly, to try and design new products that may be even more helpful in the disease.

I think that rather than suggesting doing a chemical screen of hundreds of thousands of projects, which is what many pharmaceutical companies do, and looking at a rather non-specific outcome, they would allow you to use fewer, more directed molecules and to have a much more relevant assay as the outcome. That’s important because it will speed things up.

What do you think the future holds for Huntington’s disease in the next generation?

For people who are currently in mid-life and perhaps may not have the disease or are only just beginning to get the disease, we are unlikely to have treatments that are going to immediately help delay onset.

For their children, we are likely to be able to at least help with the disease. I hesitate to say cure the disease, but I think that we ought to be able to do better than we can do at the moment because we certainly know much more about the disease.

Not just because of our work; there’s also other work going on that will allow this. There are examples of other diseases such as many of the cancers that tell you that the progress often tends to be quite incremental. You’ll get several small effects that will come together to allow a treatment.

In the case of cancer, that has actually happened over the years, probably over the last three or four decades, whereas in something like Alzheimer’s disease, that process is still only just beginning to happen.

I think we’re in the same position with Huntington’s. It’s just beginning to happen, but there are one or two advantages over Alzheimer’s disease. We know the genetic cause of this disease and can absolutely predict who is going to get it. Once we do have drugs worth having, it will be much easier to organize well powered clinical trials.

There are a number of big initiatives, some of which I’m involved with, that are aimed at organizing this so that there is a cohort of patients ready for clinical trials when the drugs become available. They are just beginning to roll through now.

Do you think your research will impact any other disease areas?

Huntington’s is not the only disease caused by expansion of repeats in the genome and it may be that it will also be possible to help with some of those other diseases, most of which are rare and many of which are genetic, using similar types of treatments that will have similar pathway involvements. We’re currently investigating that.

A treatment for any of the neurodegenerations is likely to highlight things that you might be able to do in other more common neurodegenerations.

Where can readers find more information?

Our research paper was published in Cell.

There are a number of very good websites for people who suffer from Huntington’s disease. Most countries, including the UK, have associations for patients. The one in the UK is the Huntington’s Disease Association

There is also the Enroll-HD Study, a large study funded by a philanthropic organization, a not-for-profit organization in the U.S. That is about helping people get to a clinic and get the assessments they need. In the UK, that’s perhaps a little bit less important because the NHS does provide a lot of that anyway. In some countries, many of these patients would not get these services if it were not for the Enroll-HD study, which is set up to provide an observational study of exactly how the disease progresses.

That is something you would think that we would know in detail, but actually we don’t necessarily. There are all sorts of things we don’t know about simply because, in each center, there are only a relatively small number of patients, so it’s hard to get a big picture or overview of what the disease is like on a fairly general basis.

These studies have been set up over the last ten or twenty years to try and address that, so that when you do get to perform a clinical trial in this disease, which is quite slow to progress, you do know what you should be measuring so that you can carry out a properly powered study that will give you answers about whether your potential drug will help or not, which things it will help and which things it won’t. That’s been important. There are websites for those studies as well.

About Professor Lesley JonesLesley Jones

Prof Lesley Jones is a biochemist and cell biologist who has worked on the biology of neurodegenerative diseases for over 20 years. She is particularly interested in Huntington’s disease and was one of the first to show that an early consequence of the mutation that causes the disease is changes in the way cells express their protein products. She has been involved in genetic studies in these diseases, particularly in using genetics and pathway analyses to highlight the most important biology in the diseases: much of this work involves using large scale data on the whole genome and interpreting it to make it meaningful in defining therapeutic targets. The genetic modifier study in Huntington’s disease was the result of 20 years of work: it has given us new avenues to explore for therapeutic possibilities.

April Cashin-Garbutt

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April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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