Episode 3 Bonus: Inside Clinical Trials

In our wide-ranging conversation with Professor Chris Shaw, we had enough
material for a bonus episode. Join Dr Sarah Mizielinska and Professor Chris
Shaw as they take a closer look at the different stages of clinical trials, from
early preclinical work to testing in patients. They also explore the evolving
role of animals in research, and how advances in stem cell technology are
helping scientists reduce reliance on animal models when developing new
therapies. 

Learn more:  

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🔬 UK DRI at King's: https://www.ukdri.ac.uk/centres/kings... 

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Transcript

SPEAKER_00 0:06

So you talked about the phases of these are clinical studies now. This is once we have a therapeutic, we want to get it into people, and there are these very defined stages of how to develop and test a therapeutic. Can you talk us through a little bit of those different stages?

SPEAKER_01 0:21

Yes, so obviously we do experiments in in animals to begin with, and we used the mouse knocked out for the proganulin gene to show that we could reverse pathological changes in that mouse. We managed to show that. We then wanted to go to a larger brain, which we chose the sheep, which was a much larger brain than the mouse, and we could see that the progranulin protein was expressed now around the whole brain, which was exciting. And then we went to the monkey because that's so close to the human that we could see whether there was any specific interaction that could be a risk for humans. And that gave us enough information to go to the regulatory authorities. In the UK, it's called the MHRA, and in the US the FDA. And they say, yes, this looks like a sensible and rational way, and we think you've done uh proof of safety. And then we're able to communicate to clinicians who look after patients and to ethical organizations and various hospitals and countries to say this is what we want to do. And they can review that, ask us questions, and really drill down into the evidence. And if they're happy, then they allow us to treat patients from their community. And we went to some very specialist centres that had the right scanner and the right people and expertise to be able to deliver these to the right place. So everything was about safety, and subsequently we want to know whether it works.

SPEAKER_00 1:37

Okay, so let's just take it back a little bit to this evidence, this the kind of pre-clinical evidence. So before you get to people, we're testing in animals and you're testing in cells and mice, and you mentioned monkeys and other things as well. So how how does that work? And kind of how do we know when something's good enough to take it forward to humans?

SPEAKER_01 1:59

Yes, well, obviously we want to be as safe as possible, and and so that's why we go through so many steps to do that. You know, I think in the future that is going to change. Um I think uh the trend is to use fewer and fewer animals in in research, and as our ability to take human stem cells and turn them into various cell types and tissues and even you know organ structures like small brains and a dish. Uh we're going to get closer to using just cells for the early stages and reducing the number of animals we use to a very small amount just at the very end stage. I don't think it we're likely to get to do trials of this sort of therapy without going through a few animal experiments, though.

SPEAKER_00 2:39

And so why why do you think that is? So obviously we can test quite a lot of things in in cells, as you mentioned with us amazing advancements in our modelling of human stell cells in a dish. So why do we need these animal experiments? What do they tell us that the cells cannot tell us?

SPEAKER_01 2:56

Well, obviously, um, if we're trying to reverse a disease process and your disease affects movement, you know, your your cells in a dish are not going to be walking around, right? And so you're not going to be able to show that. Um if you're trying to treat mood, depression, you know, you can't tell whether your cells are depressed or hallucinating uh or having seizures necessarily. So I think those are really important things to check. You can, of course, for the liver cells to see whether your your therapy is toxic. But even the liver is made up of different sorts of cells and a much more complex organ. So I think we're getting better at trying to make a mini organ in a dish to look at toxicity. That's really important going forward. But I still think for more complex behaviors, particularly for the brain, we're going to need some animals to really test these things out.

SPEAKER_00 3:41

So you think there'll always be a necessity for some form of step between cells and humans?

SPEAKER_01 3:46

Yes, we may not need to go to more um advanced animals like uh you know monkeys or or other higher animals, and we may uh be able to just focus on mice that are able to manifest these diseases or use the mechanisms that we do.

SPEAKER_00 4:03

And so we've talked about the advancements in stem cell models as well. So, what kind of advances are helping us not use animals to using them in a dish? We've talked about human stell cells, but what does this really mean? Like what advances are we making in these dishes that we're growing in labs?

SPEAKER_01 4:20

Well, it's amazing. So essentially, we've got a recipe book, and we can make different sorts of cells in a very specific way as individual, you know, uh sorts of single cell type cultures, but we can also get mixtures of cells, and we can actually see that these cells talk to each other as they develop, and they actually create an organ which looks very much like uh what is happening in humans and the same structure and the organization and those sorts of things. Um, and then actually you can get organs to start to talk to each other. So we can get um the kidney and the liver talking to the gut and the bladder and those sorts of tissues. So so you can start mixing the tissues together to see how they interact. And then in my own uh laboratory, we're able to take spinal cord neurons and and and supporting glial cells and connect them to muscle cells. And they do actually activate the muscles and get them to contract. Wow, that's very incredible.

SPEAKER_00 5:14

Yeah, so that's really helping us to kind of test those things. Still doesn't completely replace how all the complexity of a full organism or animal, but really helps us test parts of that complexity in a cell dish.

SPEAKER_01 5:28

Also, length of time. We know we can grow cells for a certain period of time, but actually sometimes we need to study things for a year or even several years.

SPEAKER_00 5:36

And our cells don't last that long. Our cells don't last that long. Not yet. Not yet. No. And so once we have this, so an application to what we've been talking about, some of a gene therapy in a virus, tested in some cells and maybe some animals, and we're having positive results. What do we do prior to getting that to humans? What are the steps to get that then to humans?

SPEAKER_01 5:58

So this is really important. So we we um pull together all the evidence, we say this is like to be effective and we think it's safe, and we present that to the regulatory authorities, and they go through a lot of review to really ask us questions, justify various elements of what evidence, and dig down into the strength of the evidence, and they'll either approve it or not, and get us to go back and do more experiments. We then need to go to each single country that we want to run those experiments, and they and and they have to decide whether it's safe for their patients to experience this particular therapeutic approach. And then, of course, we need to talk to the doctors that are looking after those patients to say to them, you know, is this a rational approach? You know, do you think that this is an option for your patients? Um, often, and in the situation for prograninum, there are multiple trials going on, and so you know, some involve you know giving antibodies intravenously, some involve giving tablets, and we're asking them to undergo surgery and to have a virus injected into the brain. So it's a very big ask. We also want to communicate with our patient groups and their families, and that's a really important uh area of communication because we need to talk to them about our plans going through, we need to share with them the evidence that we've got that this is a rational approach, and then help them decide of all the options what they might want to do. And that's a very personal uh decision. Um, most people are very interested in clinical trials and want to be involved if it's an option, but they really want to know about safety and is this is this the best option to choose?

SPEAKER_00 7:23

For them individually, right? Just a very individual decision. So if someone had motor neuron disease, like how would they get involved in one of these clinical trials?

SPEAKER_01 7:34

So the first is to talk to their doctors, their general practitioner, and their hospital consultant to find out what trials are out there in recruiting, to find out what that would involve, practically speaking, you know, what they would be taking, you know, what the risks are, what the pros and cons are. If there are a number of different trials, you know, what what would they choose? You know, how how would you how would you go about that? Um and and then there are patient organizations, you know, in the UK, particularly Motion Urban Disease Association, the America, the ALS Association, and they're very good as an independent source of information to say these are the options that are out there, these are the trials that are actively recruiting, this is the evidence this we think is safe, this is not necessarily safe because there have been some unsafe therapies that have been promoted in various parts of the world.

SPEAKER_00 8:17

And your your experience is interesting because you sat on both sides as the clinician where companies are coming to talk to you, and now you're on the other side also having your own company and talking to other clinicians about convincing them to use your test your therapies.

SPEAKER_01 8:30

Yes, obviously, I could never try and persuade my own patients to take the therapy that we've developed, right? So I don't ha have any involvement in those in those trials. Um but I have been on the other side now, and I've been involved in lots of clinical trials. Uh, and it and uh you know you ask the people who are presenting the evidence some pretty hard questions, and you really want to know that because you have to then relay that to your patients in an honest fashion, in an independent fashion, and what you think is safe and not safe.

SPEAKER_00 8:56

So that's what we talked about earlier, the different phases of kind of clinical studies. There's like the safety phase, and then there's the really testing if it has an effect phase. So you're in the safety phase of this at the moment, or you're doing both at the same time?

SPEAKER_01 9:09

A bit of both. So obviously we're m monitoring people's symptoms and progression, we're looking at their blood and their spinal fluid to see whether there are any response there. Uh, and also we're looking at the the brain uh by scanning to see whether there are, you know, these conditions are parts of the brain shrink, we see whether we can arrest the shrinking of the brain.

SPEAKER_00 9:28

So is that that's the the measurements then? This is the so how do you tell whether the therapy is effective? How what are the kind of key outputs that we look for to see if something's effective?

SPEAKER_01 9:40

So when a degenerative process is happening in the brain, we see proteins released from nerve cells in the bloodstream and the spinal fluid. So if those were to go down, then that would suggest that fewer neurons are dying. That's a pus. Um, we can also look at um whether the protein, in particular progranulin, is going up in the spinal fluid. And that would tell us that we're getting the protein made by our factory and it's getting around the nervous system. So that would be exciting. And then with the MRI scans, you know, if we can see that the rate of shrinkage in the brain is is slowing down, then we can say that looks positive. Now, the most important thing is then testing people in terms of the language skills and the behavioural skills, behaviors as to whether that's changed. You know, we talk to the patient, we talk to the families, and we get some measure about whether we're seeing a clinical benefit. So all those things together will help us. Um, the the earliest signals will come from um the bloodstream in particular, and the next signal I think would come from the scans. But the most important signal is where the patients actually feel an improvement and their families notice a difference.

SPEAKER_00 10:42

Yeah, and those symptoms you you spoke to are related to frontotemporal dementia, so they are the personality, behavior, and language skills. Whereas in motor neuron disease, that would more be movement and motor function and breathing and things like this, wouldn't it? So, and that would be things to come.