Improving Riluzole for MND

Victoria Pugh is studying for her PhD at the Universities of Bradford and Reading, which is funded by the MND Association. Under the leadership of Prof Marcus Rattray she is looking at the drug riluzole and how to make it better. Victoria also presented a poster of her research during the 24th International Symposium on ALS/MND in December 2013. Here, Victoria explains her project and the life of a PhD student.

How did I get here?

My interest in biology started at school and from this I decided to study biomedical sciences at university. While doing my undergraduate degree I became particularly interested in all aspects of neurodegenerative diseases, from their biological basis to their effects on patients. As well as learning about the pathology of Alzheimer’s, Huntington’s and Parkinson’s Disease I also had the opportunity to meet people living with them, which further rooted my interest.  On graduation I was given the opportunity to study for a PhD based on treatments for motor neurone disease (MND).

What’s my PhD about?

The aim of my PhD is to improve the treatment currently available for MND. Riluzole, the only drug currently available for treatment of MND, could be better. The extent to which it extends life in patients is limited, it has many undesirable side effects, and is not suitable in all cases of MND. Despite this, the mechanism through which riluzole provides protection to motor neurones appears to precisely target a range of malfunctioning cellular processes within motor neurones which are responsible for the neurodegeneration in MND.

A grant from the ALSA, the American MND charity, is funding work by a chemist, Tes Matthews, in creating novel riluzole derivatives, i.e. drugs with the same base structure as riluzole but with additional chemical groups. By only slightly modifying the original structure of riluzole the aim is to generate new drugs that act in a similar way to riluzole, targeting the same malfunctioning cellular processes. However we hope that these alterations will result in the new drugs having a higher affinity for the cellular targets than riluzole. Putting an analogy to this idea, if the shape of riluzole as a drug was circular it would comfortably fit through a large square hole but would not be a precise fit. In contrast the new modified drugs in this analogy would be square-shaped with the same dimensions as the hole fitting it perfectly. With this aim we hope the new drugs will have a greater effect towards restoring normality in the neurones, or at the least halting the degradative processes of MND, therefore being a better treatment against motor neurone loss.

Alongside the grant from the ALSA, we received a co-funded grant from the MND Association, in combination with a studentship from Reading University. This grant is funding my research to test the potential new drugs in both cortical neurones, found in the brain, and spinal motor neurones in order to determine whether they are more protective against cell death than riluzole.

In my work I am primarily using cortical neurones, as preparation of these cells results in a higher yield in comparison to motor neurones so work can progress much faster than if using motor neurones alone. Furthermore the two neurone types share many characteristics meaning that all the results I achieve using cortical neurones are likely to be applicable to motor neurones. In addition the protocol for generating cortical neurones was already in place in the lab when I arrived, whereas the preparation of motor neurones is much more complex and unique to my project alone therefore training was delayed until I was comfortable with the cortical neurone preparation.

In order to test the new compounds I expose both types of neurone to a neurotoxin which induces cell death in a manner similar to that seen in motor neurones in MND. I then treat these cells with riluzole or the newly synthesised derivatives of riluzole with the aim of preventing the neurotoxin induced cell death. Using imaging techniques I can determine the level of cell death following treatment with the neurotoxin alone in comparison to the cell death in the presence of either riluzole or the new drugs.

As is the case with all research, progress is slow due to unforeseen problems .For example  I initially had a lot of trouble with keeping the cortical neurones alive for long enough to use in my experiments, each week altering one part of the protocol convinced that would solve it, and each week finding that wasn’t the case.  However this has now been overcome, and I have also mastered the growing of motor neurones, so although progress can be slow, it is still progress!

Putting my research into perspective

When I started my PhD I knew very little about MND and had never met anyone living with it. In May 2012 I attended the MND Association Spring Conference in Taunton with my supervisor Prof Marcus Rattray, and had the opportunity to speak to a few people living with MND. They gave me a new sense of appreciation of the disease and the people who are fighting it. In a way the conference has allowed me to ‘put a face’ to my research. It’s all well and good reading about MND but meeting those living with it really highlights the devastation the disease can bring about and it has made me even more determined and appreciative of the work I am doing.

Furthermore the spring conference broadened my understanding of the work carried out by the MND Association which I was never truly aware of. The amount of aid provided by the MND Association in terms of care centres for patients as well as providing support for carers is remarkable.

Despite being unfamiliar with MND when I started my PhD in October 2011 I have learnt a lot about the disease on a scientific, clinical and social level. I am honoured and delighted to have the opportunity to be doing a PhD, particularly one centred around such an important cause.

My first symposium

In December I presented a poster at the 24th International Symposium on ALS/MND. This was my first time at the symposium and although I was slightly nervous about presenting my work it was a good opportunity to discuss my work with my peers to discuss ideas and suggestions of ways I could move forward in my project. The conference also allowed me to gain insight into other work in the field in a broader aspect than I usually read up on. I came away from the conference with renewed confidence and enthusiasm about my project with a list of fresh ideas to begin working on this year.