New targets for epilepsy treatment

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Epilepsy is an electrical disorder of the brain causing debilitating seizures and affects around two percent of the population. It’s a devastating disease that arises in many forms, with no cure for most.

Associate Professor Chris Reid is a Principal Research Fellow, member of Faculty and Head of the Neurophysiology of Excitable Networks Laboratory at the Florey Institute of Neuroscience and Mental Health. Chris Reid is currently developing a new treatment for epilepsy and his research project is part of BioCurate’s research portfolio that spans across several therapeutic areas, from oncology to central nervous system, to musculoskeletal and fibrosis. BioCurate is an independently-operated venture catalyst jointly formed by the University of Melbourne and Monash University.

Dr Andi Horvath sat down for a Zoom chat with Associate Professor Chris Reid.

ANDI HORVATH
Chris, how prevalent is epilepsy in Australia, and actually around the world?

CHRIS REID
Epilepsy is one of the more common neurological disorders. There's at least 150,000 people in Australia currently suffering from the disease. Worldwide, that increases to about 50 million. Interestingly enough, it's actually perhaps more prevalent in developing countries where nutrition is poor, and clearly healthcare is poor as well. It's very much a very common neurological disorder.

ANDI HORVATH
Chris, when you mean common, can you give it to us in terms of per head population?

CHRIS REID
Well, I said about 150,000 Australians do suffer from the disease, so that gives you a rough estimate. Across a lifetime, about three to four per cent of people will have a seizure. Interestingly, the predominance of those seizures tend to occur either early in life, and then again towards the end of later life as well. About four per cent of people will have a seizure at some point in their life.

ANDI HORVATH

Currently, what is the treatment we use for human epilepsy?



CHRIS REID

One of the big issues with epilepsy is - at least a proportion of patients, about a third of patients are refractory to the current treatments. Those treatments are wide and varied. They include drug therapy. They also include invasive things such as having surgical removal of parts of the brain. There's also diet versions. There's a well-recognised ketogenic diet which is known to be quite effective in certain types of epilepsies.

There is a broad range of methods to try and treat the disease. Generally speaking, about a third are not responding particularly well to any of those therapies.

ANDI HORVATH
Chris, what attracted you to this area of research? You're interested in neurophysiology. Tell us more about your foray into this area.


CHRIS REID
I actually did pharmacy as an undergraduate, and then worked as a pharmacist for a period of time. During that time, I actually worked within the hospital setting, in a neurological ward in particular. I saw a series of patients who were just not treatable. That was a few years ago now, and thought well I can only do so much as a pharmacist. I would like to actually do something at a more fundamental level. I deviated a little bit and went into much more basic neuroscience. I went into mechanisms underlying [learning] and memory. I did a great postdoc in London.

When I came back to Australia, which is in about 2001, I really felt like I needed to get back to my clinical roots, for the reasons I went back into science in the first place. That's where I came across a couple of people, Steve Petrou and Sam Berkovic. I was quite a young scientist at that point, and they had a very big, or strong focus, on genetic epilepsies. That really focused my attention into the epilepsies, with which I've been working for now in excess of 15 years.

ANDI HORVATH
Wow. Chris you were inspired by people you couldn't help as a pharmacist, and then you moved into scientific research. Did you enter the field of epilepsy research straightaway?


CHRIS REID

Not immediately. A lot of my early work was very, very basic science. I actually looked into a form of synaptic plasticity called long term potentiation, which helps synapses become strengthened under certain learning paradigms. My very early focus was very, very basic neuroscience. Trying to understand the basic building blocks, effectively, of what a brain is. My drawback into the more clinical-relevant aspect was really driven by that original need to go into science when I came back to Australia in about 2001. As I said, that's when I met quite important people in the field of epilepsy that inspired me further.

ANDI HORVATH
Okay, so you're interested in the way nerves synapse with each other, the connections, and how they find a way of transmitting their messages. What led you towards a rat model of epilepsy?


CHRIS REID
Clinical research is essential to the way we do science. However, there's only so much you can do in a clinical setting. Much of what we need to understand in the brain needs to be done with much more invasive techniques. The technique that I'm specifically an expert at is a thing called electrophysiology. We actually take bits of the brain from a mouse and/or rat. Put little pieces of glass on those neurons within that slice, and we can record the electrical activity.

We know that epilepsy is an electrical disease. When we have a seizure, the brain goes into these hypersynchronous episodes. That hypersynchronicity needs to be recorded in electrical terms. That's the big reason for going into a mouse model. We have the ability to be more invasive, and use much finer tools to understand the disease.

ANDI HORVATH
The burning question is are we any closer to finding new treatments for epilepsy?



CHRIS REID
There's two parts to that answer with regards to my research. The first relates to the genetics of epilepsy. I've been very fortunate to be part of the genetic revolution which was started by Sam Berkovic and Ingrid Scheffer from the University of Melbourne. I joined Steve Petrou's lab at a time when that was very new. We generated mice models based on genetic mutations in humans. Those mutations, or those mice, are particularly impressive in the sense that they recapitulate much of what you see in a human. Meaning that we have very good models to understand the disease. In that front, things have moved incredibly quickly over the last 25 years, which is when the first epilepsy gene was discovered, to a point now where gene therapy is becoming a reality.

The gene therapy for a subset of epilepsies is starting to look very promising. We are expecting, I think within the next three to five years, therapeutic approaches around gene therapy that will be effective. The small downside to that is that the genetic architecture for the less common epilepsies is starting to be well understood. For the more common epilepsies, it's less well understood.

We do need alternative approaches as well which is really the program that I've been driving with BioCurate. That is to try and discover small molecules. In that particular case, what we've done is actually identified a channel in the brain that's in a hotspot that causes seizure generalisation. That's when seizures cause the big tonic-clonic seizure that we mostly associate with epilepsy. With BioCurate, we're actually doing a chemical, or a small molecule program, to design drugs to that target with the view of treating a larger population of epilepsy people. Two-pronged approach, both of which have their risks, but both of which are moving forward particularly well.

ANDI HORVATH
Chris, it seems that a lot of research starts to really emerge into the clinical setting with collaborations. Tell us more about how multidisciplinary approaches like BioCurate can actually help these things come to market?



CHRIS REID
That collaboration occurs at numerous levels. The collaboration that we're doing really in the genetic world is the clinicians finding genes, and us then taking those genes and incorporating them into mice models. Understanding the mechanisms of those causes of the disease through that genetic mutation. Then, because we can identify mechanisms, we can give indications of what would be a good therapy. Either through gene therapy or repurposing old drugs, for example. That's a very clear circular collaboration in the sense that the clinicians give us information, we use it to then give them information to treat patients.

BioCurate is slightly different in the sense that we know as a scientific community that translation is central to (1) our survival, but (2) our worth. Australia's historically not been very good at translating their ideas into products. BioCurate's been spectacular for my research for a number of reasons. The first is money. Research can't be done without money. They are financing a small molecule program, so we're thankful for that. It goes beyond that. As a basic scientist, we don't get taught the process of translation. It's not something that - it probably doesn't even interest most of us to be fair. We're interested in our little puzzles, and we're interested in getting those little puzzles into a paper, and then getting the grant.

BioCurate provide a different forum. They provide structure, they provide a pathway, they provide also an academic input as well. A lot of the chemistry's been driven by BioCurate chemists. It's an all-inclusive collaboration that really gives us the best possible chance of taking my very basic idea - which I found in addition in mouse models - through to a point of creating a drug. Beyond that, the translational part beyond that, is even more complicated. Regulatory, whether the drug is able to cross blood-brain barrier. All those types of things are things that I don't have expertise in, and that BioCurate are providing.

ANDI HORVATH

I think that's really good news. When I first started science journalism, everyone was saying in R&D, the research and development, the D part was missing. It's really great to see and hear about Australia picking up the reins of development. You've predicted that we might have something in three to five years. That's pretty good news.

CHRIS REID
Yeah, with all the caveats. I think as basic scientists, we've got to be clear that what we're talking about is risky. There is always a long road. Often a lot longer road than you ever anticipate, from getting an idea in a laboratory, through to something that might end up in the patient. I think the three to five years is more for the genetic therapies that have been developed. Those are very targeted. We know exactly what mutation's causing the disease. The gene therapies are very targeted to those genes, so that's a big plus. As said, they’re not going to be treating the vast majority of epilepsy patients. The small molecule program will probably take longer, realistically. We've got timeframes on that between seven and eight years for development of a drug, although the hope is to perhaps to bring that in a little earlier.

That said, it's moving. We've been working with BioCurate now for less than a year. Already we're generating lead compounds that have promise, so who knows. The hope is certainly within three to five years for the genetics, and maybe five to eight years for the small molecule program that's being run through my laboratory.

ANDI HORVATH
Chris, what would you like to see activated in society?

CHRIS REID

One thing I wouldn't mind using this forum to get across is that basic science is a central engine to innovation. A lot of our funding bodies have been focused heavily on translation. I think that's important and critical. BioCurate is an example of that. We've got to be careful that we're not throwing the baby out with the bath water. I wouldn't mind using this as an opportunity for advocacy of basic science. The need to have people play and look and find things that weren't expected is central to the development of new targets. It's central to our understanding of how the brain works. It's central to the development of newer drugs into the future. I believe that Australia should be very, very focused on the support of basic science.



ANDI HORVATH
Chris, what's your advice to future students?

CHRIS REID
Science is a spectacularly exciting job. I think it must be one of the best jobs in the world. To wake up every morning, have an idea, and have the ability to translate that idea into something real is, I know, for me at least, is one of the most exciting things that you could possibly do. Students that have that need to know, have that want of freedom, I couldn't more highly recommend a scientific career.

The one, I guess, caveat to that - and it's something that we do need to bear in mind - is that it is a very competitive field - because the job's so good -which means that the career can be a little bit finicky. You're not always guaranteed to have money. If you've got passion, and you've got a desire to really change the world, you will make a career out of science. It's certainly a career that I've had, and enjoyed for over two decades now. It's been particularly exciting.

The other aspect of it as well is if it's international. As a student you're really focused on what you're doing within that quite narrow environment. As you become a postdoc, you head overseas. You work for three or four years in either New York or London - I was in London for three years for example - you really do grow as a person. Highly recommended as a career, with the realisation that it's not an easy one.



ANDI HORVATH
Chris, what would you like us to think about next time we encounter epilepsy in society, or know a friend who has it?



CHRIS REID
One thing I wouldn't mind getting across from an epilepsy perspective, and this is something that I've now got a personal connection with.

A father contacted me a few years ago about a little girl called Ebony. Ebony has a mutation in the gene that I'm particularly interested in. It's the reason that we got together. We actually made the Ebony mouse. I'll call it the Ebony mouse because the mum and dad have seen the mouse, and they actually name it the Ebony mouse. That mouse is telling us a lot about what's happening with Ebony. It's giving us an opportunity to potentially help her.

What really came to the fore with that interaction was just how tough it is for these people. Not just for the kids themselves, but the parents are going through - Ebony will have clusters of seizures that occur 20 or 30 at a time within a day. Sometimes she goes blue. Sometimes she has aspiration pneumonia and ends up in hospital.

That aspect of it is hidden from much of society. Having that interaction, which is unusual for a scientist, that one-to-one interaction. It's really highlighted just how tough it is for people not only having epilepsy, but people that are looking after, especially young children, that have epilepsy as well. That's what I would like people to think about. The difficulties that these people are facing.



ANDI HORVATH
Associate Professor Chris Reid, thank you very much.

CHRIS REID
Thank you very much. 


CHRIS HATZIS
Thank you to Associate Professor Chris Reid, Principal Research Fellow, member of Faculty and Head of the Neurophysiology of Excitable Networks Laboratory at the Florey Institute of Neuroscience and Mental Health. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on August 6, 2020. You’ll find a full transcript on the Pursuit website. Production, audio engineering and editing by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis. Join us again next time for another Eavesdrop on Experts.