The 2022 Sheila Essey Award Winner

Research

The American Academy of Neurology, The ALS Association and the American Brain Foundation have awarded the 2022 Sheila Essey Award to Matthew Kiernan of the Brain and Mind Centre at the University of Sydney in Australia and a member of the American Academy of Neurology.

The Sheila Essey Award for ALS research is granted by the American Brain Foundation and made possible through the generosity of the Essey Family Fund through The ALS Association Golden West Chapter, in memory of Sheila Essey, who battled ALS for 10 years and died from the disease in 2004.

We recently caught up with Dr. Kiernan on Connecting ALS to discuss advances in ALS research since he first entered the field and how the Essey Award will help move his research forward.

What brought you into the field of ALS research?
I'm a neurologist by discipline and training, and it was during my general medical training, that in fact, I owe a debt to the United States, and it was George Bush Sr. who was president at the time in the 1990s, and he declared it the decade of the brain. And it just seemed very exciting. I mean, there was the discussion that imaging techniques would come along, there'd be magnetic resonance imaging, we'd have pictures of the brain in front of us. The Human Genome Project was well underway, so we'd understand the genetic basis for a lot of the conditions we're dealing with.

And really, just seemed that, as a result, we were going to have a lot of therapies. And I suppose many of the other systems in medicine have been well worked out. Cardiology and the studies there, the research is more involved with tens of thousands of patients looking at slight variations in blood pressure. But really, we didn't understand how the brain works, mechanisms of the brain, the concepts of brain and mind, and then healthy brain aging, and what do we do with neurological neurodegenerative conditions? So, I thought it was like a wide open road, relatively unexplored and exciting. And so, that's why I chose neurology.

Then, I suppose, why did I get into ALS and neurodegenerative diseases? And I started after I did my clinical training, I did a period of research. And at this stage, we were trying to uncover why nerves stopped working, conduction failure in nerves. And gradually, I became aware of a whole field -- series of conditions. At that stage, I had seen quite a bit of ALS, but it was presented to me as a neuromuscular condition, a problem with muscle wasting. And I was doing a lot of neurophysiology as well. So, diagnostic testing. And I always assumed it was a so wasting disease, and clearly it is, but then people started to bring up concepts, well, where does it begin? Is it really beginning in the muscles or the nerves, or is it coming from the spinal cord? And there weren't many people who were saying that it was coming from the brain.

And in fact, when some of those people would get up at conferences saying that it's coming from the brain, they'd be shouted down or even ridiculed. And one of the other arguments at that stage was, I remember a quote from David Niven, the famous English actor, and he said, "It's horrible being trapped in a body, but your mind is intact."

And that was the understanding, that the brain is still working completely normally, but there's a muscle wasting and a paralysis and a locked-in syndrome. And I think during the course of my career, it's been amazing to see the whole turnaround of the condition to now understanding that it is a primary neurodegenerative disease that begins in the brain, spreads through the whole neuro pathway and network, particularly the corticospinal tract, which controls voluntary muscles. So, obviously muscle wasting is a key feature of the disease.

And I think also with that, then the links to dementia, frontotemporal dementia. And it turns out that people had discussed this, but because of the burden of the disease, ALS, they'd been reluctant to investigate it, because they didn't want to put more sort of a stigma on ALS patients. And so, the people who wrote the original studies, at least in the English literature, said they gave it away because it was too hard, too complicated, and they didn't want to explore behavioral abnormalities in ALS patients.

And I think now with the discovery C9orf, C9 Open Reading Frame gene, which causes both frontotemporal dementia and ALS, it causes such a significant proportion of disease in patients that we see with apparently sporadic disease, as well as familial ALS. I think, again, now we understand how cognition is a critical part of understanding the condition. So, the field has moved. Unfortunately though, we still don't have a very fine point to say, "Yep, this is how ALS begins, and this is how it progresses through the body." And that's what has really slowed us down in terms of discovering better therapies for our patients.

Talk to us a little bit about the research that you're doing today.
My path is as a clinician, as a neurologist. So my path is very much driven by patients. Their families, carers. And I suppose that's also an important thing to raise, that ALS does appear to be a uniquely human condition. Of course, there are models, and there are animal models of the disease. Unfortunately, a lot of the therapies that have worked in animal models have not translated into a therapy for patients.

So, I think it's important to always try to make sure that we're focusing on the human disease that is ALS. As I mentioned, I was interested in neurophysiology, and a lot of the techniques were more driven in limbs and spinal areas, but I was interested then in trying to get to the brain. And our brain, courtesy of evolution, is very well protected. It's hard to get to.

And one of the ways that we can activate the brain is through a technical transcranial magnetic stimulation. So, we get a magnetic stimulator -- it's not invasive -- and it's placed over parts of the brain to activate them. So, we can activate the motor neuron in the brain and look at the behavior. And so, that's what I've focused really the last 25 years on, is trying to come up with techniques. Well, firstly, to make the technique useful for ALS. Secondly, to use it to explore what's going on.

And so, we have developed a technique called transcranial or threshold tracking transcranial magnetic stimulation. So, it's all now completely automated on a computer like a PC, driving the whole regime. And we use it for all of our patients when we first see them to try and work out whether it is ALS or not. And there's a very typical signature of ALS patients when you do transcranial magnetic stimulation, their brain is hyper excitable, so it takes very little to activate the motor neuron. And that hyperexcitability is almost like a stream flowing through the brain, spinal cord, and peripheral nerves.

And we see that peripherally, because they have overactivity, the patients have fasciculations, sort of the muscles and nerves are firing off by themselves. And that's the same in the central nervous system. There's a hyper excitability. So, that's been the focus of my own clinical research. But then obviously, with colleagues, we've been undertaking national and international clinical trials. And then we're trying to come up with appropriate biomarkers to try and work out, firstly, diagnostic issues, but also prognostic.

And then the next, the other issue that I would like to raise is diagnostic criteria. And I think that has held us back as a field. It was always complicated because we didn't have a test to run. You can't send someone to the pathology and they come back and they say, "Yes, it's ALS." So, inevitably, we are trying to work out criteria. And those criteria were done in a very appropriate way to say, "Well, if we put this patient into a clinical trial, this is what we say they have." When I say "We" it's the people who are running the clinical trial.

But they started off with various degrees of certainty, from possible, probable, to definite. And I think in a way, and it's clear why that happened, but that has also been a slight problem for both the clinicians and patients, because some people are saying they're using that as... Well, it's not definite ALS. And well, what is definite ALS? It turns out that if one or two neurologists say that it's ALS, they're about 95 to 96% correct. So, a lot of patients were then not having definite or probable ALS, and many patients were actually dying without going through the full criteria of being diagnosed.

So, we realized this was a problem. We held a workshop in 2019. It was in the Gold Coast, it was supported very generously by The ALS Association, also the World Federation of Neurology, PACTALS, which is PanAsian Consortium. We've got 30 representatives through, and some of them had been present on each of the criteria from Airlie House, through to Awaji, and the El Escorial Criteria. And we stripped it right back and came up with what are now called the Gold Coast Criteria. Which basically says that ALS is a progressive disease. So, if it's not progressive, it's not ALS. And it has the features of central and peripheral involvement or upper and lower motor neuron abnormalities, and other conditions have been excluded. So, it's a very simple set of criteria.

And what I hope with those criteria is that it facilitates patient recruitment and enrollment in clinical trials. So, I think all of us as a community want every patient to be offered access to involvement in a clinical trial. And this is, I think, very important, not just for the discovery and the patient feeling of contribution and autonomy, it's also that any patient who is on a clinical trial does better than patients who aren't on a clinical trial. And we're seeing now every single clinical trial, if there's a placebo arm, those patients are doing better and better and better with every clinical trial. And I think that's because they're being monitored, they're actively engaged with their clinical team, and they feel that they're contributing. So, I think that's a major plus.

What is different now from when you first started in this space?
To put some perspective, multiple sclerosis, no registered therapy in 1990, now we have about 13 registered therapies, and some of those therapies can be given in the first attack for a patient and they never have another episode in the course of their life. Stroke, stroke neurologists are removing clots from the brain acutely and patients leave hospital one or two days later without any deficit. So, the field, in general, has moved amazingly. In terms of ALS, it was regarded as a very hard and negative. And at that stage, there was nothing offered for patients. And once the diagnosis was made, and I've seen this, so it's not some sort of make believe, it was get your affairs in order, this is a relentlessly progressive disease, and there's nothing that we can do.

And I think to take to extinguish hope for patients and their families is very cruel. I think that what has happened is, there's been a major movement worldwide. There's been an interest in trying to solve the seemingly unsolvable problems. And ALS has gone from being relatively unknown to now being incredibly well known worldwide. And I think the Ice Bucket Challenge and all the various other philanthropic approaches has certainly increased visibility of ALS.

We have managed internationally to band together. We all work very collaboratively, and patients are the core of all of those initiatives. For instance, in our international symposia, patients, fellows who come along and they help guide the research. And I think the turnaround from basically having no involvement and being harsh with patients has been completely turned. Patients are driving the whole research agenda and are key parts of it.

So, I think we have now national registries. We understand the course of the disease. So, with these large scale, like particularly say the ENCALS model, they can basically identify to the day, virtually what the prognosis of patients will be.

Then you might say, well, okay, what are we doing on the therapeutic front? And okay, there has been some progress. In the early 1990s, we were part of the Riluzole studies. And that I think made us all think that this is going to be something very positive coming through, and that was FDA approved. Then nothing until Edaravone was the second medication that was approved by the FDA. But because of the significant investment from industry and philanthropy, there are so many trials underway, and there's a lot of medications and approaches that are very close to joining those two medications in terms of FDA approval.

And I think that we are really coming into a world that's similar to oncology, we'll have a realm of medications that we can offer. It might be that we use three or four simultaneously, it might be that we know certain medications more useful for certain patients. So, one trial that we're embarking on now relates to lithium therapy, and whilst that study in all ALS patients was a negative study, subsequent analysis of the data is showing that those patients who have a snip UNC13A, do well on lithium therapy.

So, now what we want to do is test all of our patients, and we think it's somewhere between 7 and 15% will have UNC13A, and put them on lithium. So, this is a very precision driven approach for a set subgroup of patients. And I think we're going to see more and more of that. We also know through the discovery of the genes linked to ALS, that genetic approaches, whether it's splicing techniques in RNA, whether it's ASO approaches, antisense-oligonucleotide approaches for specific genetic mutations, like C9, SOD1, I think we're going to see these introduced to the clinic. And I think that this is going to amazingly transform outcomes for ALS patients.

What impact will the Essey Prize have on your work going forward?
Firstly, I would say thank you to The ALS Association and obviously to the American Academy of Neurology, and particularly the Essey family who came up with this very generous philanthropic idea to support ALS researchers. At a very simple level, it attracts more attention to the field of ALS. So certainly, social media locally, in Australia, in the United States, this has gone around the world, and I've been very fortunate to be a recipient of this prize and join my colleagues and peers over past years.

Now, what does it mean? Well, I think firstly, it's a very generous gift. And with that gift, I'm focusing particularly on two areas. Firstly, we, here in Australia, are establishing a National Consortium for Clinical Trials, similar to the NEALS Consortium, and the Essey Prize will be used to help me progress that further.

And separately, I mentioned this transcranial magnetic stimulation technique, and we're working with our colleagues in a European firm called Neurosoft. We want to give it to all the clinics around the world to help drive more discovery, understanding of the mechanisms of the disease, and use it as a marker in clinical trials. So it's great. I think the award as well is a reflection on my own teachers and my family and the patients who have contributed to the research and their carers. And everyone got a buzz out of it and it's great to see. So, it's really a reflection of that large network. And it's great. It's always nice to have a period where there can be a bit of thanking the people who have been instrumental in your career.

Comments

Submitted by: Geraldine B. on Mon, 04/04/2022

I have been diagnosed that I have ALS.
Ihave neuropathy in both legs and I am very unsteady. It is very difficult to walk. I do not have use of my right hand. I am now working with aDr. in Chicago and the ALS clinic also. I am taking Riluzole but I don't know if it is doing anything Will this process be coming to the Chicago area and if so when and where.

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