Advances and challenges in MND research
NR Times speaks to Dr Brian Dickie, director of research development at the MND Association.
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The MND Association has announced £5 million funding to create a network of researchers and care teams that will work to increase access to clinical trials for patients with motor neurone disease (MND).
With more than 5,000 adults in the UK affected by the fatal and rapidly progressing disease, the new funding aims to enable access to clinical trials for everyone diagnosed with MND to take part in vital research.
Through the funding, the MND Association is building a coordinated network of research nurses across England, Wales and Northern Ireland. The network of research nurses will support patients in navigating clinical trials, as well as support the sharing of outcomes to help successful research be put into practice.
We sat down with Dr Brian Dickie to find out more about plans for the funding and what the current state of care and research looks like for patients living with MND.
What are the current gaps and challenges for MND research, and how will the new network of research nurses address them?
For many years, we've provided funding for 22 care centres and networks that see at least 80% of people living with MND across England, Wales and Northern Ireland.
Survival for MND is about 18 months on average from diagnosis, so, timely and coordinated multidisciplinary care is absolutely essential because the needs of people with MND are many and varied and often quite rapidly changing.
The premise behind the care centres and networks is to provide that tightly coordinated multidisciplinary care. Now, of course, the centre's do have another incredibly valuable research resource which is relatively large numbers of people with this relatively rare disease coming through the doors.
It's a fantastic opportunity for conducting research, but it hasn't been particularly well supported in the past and it's been done very much on a “trial by trial” basis. In other words, if there's a research study that comes along, the funders will put money in and then the lead centre will allocate to other centres that are happy to participate. Once the study comes to an end, the whole thing will dissolve.
If we develop the infrastructure across the network of having research nurses embedded within the care, then that will actually make it more sustainable and help to attract more studies, as well as making it a little more efficient because you're not having to constantly rebuild and attract new staff.
The key issue is that within the NHS, there are research staff that are quite generic, who are not necessarily linked to a particular condition. We're looking to help to upskill staff in MND by having this dedicated network and embedding research within this multidisciplinary care model.
Anybody diagnosed with this disease should be offered high quality specialist multidisciplinary care, but also the opportunity to participate in research and participate in research that is reasonably local, as, going from Penzance to Oxford or London or even Sheffield, especially if you have MND, is a real burden.
What we hope to do in this country is create a fertile environment that encourages drug companies to come to the UK so people with MND in England, Wales and Northern Ireland, have more chances to participate in trials.
"Anybody diagnosed with this disease should be offered high quality specialist multidisciplinary care, but also the opportunity to participate in research."
How is the current search for an MND cure progressing, and what lines of investigation may be looking hopeful?
There has been an explosion of new knowledge of MND in recent years. If you look at the number of scientific and medical publications, it has risen exponentially in the last couple of decades. MND has really moved over the past 20 to 25 years from a “Cinderella disease”, a scientific backwater, to the forefront of neurodegenerative disease, and a lot of that has been driven by research into the genetics of MND.
There's a genetic component to most neurodegenerative diseases and perhaps MND sits in that sweet spot where we know that in about 10% of cases there's a strong family history. Through genome sequencing, we've identified at least 30 genes linked to the disease and we're identifying new biochemical pathways that are going wrong within motor neurons.
So, I think it's being seen more as the testbed for a lot of translational research, taking the knowledge and getting a better understanding about what we can do about it, as well as increasing our understanding about the disease.
We're now seeing this shift towards drug discovery and development, and one of the things the Association is doing in collaboration with other organisations is investing £50m in MND research over the next few years.
The conveyor belt of interesting ideas coming out of the university labs is starting to fill up and that's another reason for creating the network.
This also links to the government as there is a programme that was announced last year called Experts-ALS. Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, about 95%. The programme has the largest ever government award for an MND research project and it's going to be topped up by charities. It is effectively a new experimental medicine platform where you might take 50 patients and give them an experimental drug, so it's not a randomised placebo controlled trial.
Instead of looking to see whether a drug is changing disease progression, which often takes a long time, we’re going to look at a biomarker in the blood of the patients, something called Neurofilament light (NfL) that's an indicator of nerve cell damage.
Neurofilament shouldn't be in the blood, they should be in nerve cells. If you find them in the blood that means that the nerve cells are degenerating, so, the higher the levels of neurofilament, the greater the damage and the faster the disease progresses.
What we want to do here is to test a drug and see if the neurofilament levels change, because they could change within three or four months. If they go down, then there's an indicator that there's protection of the nerve cells occurring. If it goes up, that's an indicator that you might actually be causing more damage and that's always a risk with drug trials.
"We're moving into an era of precision medicine."
Do you use AI in the process?
Yeah, we do in the academic labs. The use of AI at the moment is more linked to the clinical features of the disease, trying to stratify the patients into different subgroups.
A little bit like cancer, which is many diseases, MND isn't one disease. It's many different variations of a theme, and the chances are that a particular drug or a combination of drugs will be more effective in some subgroups than others. So we're moving into an era of precision medicine.
In fact, there's one good example of that at the moment that's being reviewed by NICE, a drug called Tofersen which specifically targets causes of MND. It effectively switches off the activity of a gene which is having a toxic effect, and the effects of the drug are looking incredibly promising.
What do you see as the biggest barriers for MND research?
The key one is ensuring that we find better biomarkers. We have neurofilaments which is good, but we probably need more specific biomarkers that tell us more about the different drugs that are being, or are going to be, tested.
Maybe some of the drugs that have been tested in the past would actually have been effective but were given too late, so we need to diagnose the disease faster. Biomarkers are a part of that, they help diagnosis and also could predict how the disease is likely to progress.
It could be useful for advanced care planning and trying to prevent the preventable which might happen three months six months down the line.
Then you've got biomarkers of targeted engagement. For example, is your drug actually doing as it's supposed to. Then there are biomarkers of efficacy which could show if the drug is reducing inflammation or causing the regrowth of nerve cells. This is a big area that the Association and others are investing in heavily.
Are there current drugs or drugs in development that can increase life expectancy for MND patients?
There is a drug that's been around for about 25 years now called riluzole which is a standard treatment, but it only has a modest effect. It probably extends survival by three to six months.
Unfortunately, we've had trial after trial after trial, which invariably has been negative or inconclusive. So we need to get a bit smarter, we need to be better at picking winners and that's why there's a lot more work going on in the drug discovery and development stages, bringing academics with the best ideas in to engage with industry as well.
We've worked with the likes of the UK medicines discovery catapult to develop a set of guidelines for preclinical drug development in MND. In other words, what is the minimum viable, preclinical package that drug companies would say looks good and would take to trial because of course, as you go from lab to clinic, the costs just go shooting up.
Is genetic medicine being looked at for the treatment or prevention of MND?
Gene therapy strategies are being pursued quite actively by the drug industry and we are seeing these strategies being advanced for some of the rare, inherited forms of the disease.
We are co-funding work at the University of Sheffield with a company that is developing a gene therapy approach targeting a specific form of the disease.
And then there's gene mutations which can cause MND and ALS under the age of 30. Sometimes in teens, but it's very rare, less than 0.5% of all cases. However, there's a gene therapy that's being tested for this at the moment.
We have to wait for the full trial results, but certainly, neurologists are seeing some things they've never seen before.
Rehabilitation has been one of these words I've always been very uncomfortable with saying in regards to MND, when it's a progressive disease. It is not like a stroke where the damage is done and you have an opportunity to try and improve things.
With MND, it's going to get worse and worse and worse, but maybe in 10 years time we will be using the word rehabilitation frequently and freely.
"The train is heading in the right direction and it's picking up speed."
In light of increasing celebrities drawing attention to MND, what is the public’s current awareness of the condition and what impact is this having on funding?
Public awareness of MND is quite high and there are many sports stars getting involved in raising awareness.
Research is expensive. It costs money. So the more money that charities can generate, the better, but it also gives us the opportunity to make the case to the government as well. I think if you can crack MND, then you can crack these other major neurodegenerative diseases like Parkinson's and Alzheimer's.
We might not see the light at the end of the tunnel yet but the train is heading in the right direction and it's picking up speed.
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