Could a One-Time Brain Injection Replace a Lifetime of Medication? | Gene Therapy Explained

Welcome to the third episode of Between the Signals, a podcast brought to you by the UK Dementia Research Institute at King’s College London. In this episode, we explore how fundamental research gets turned into medicine.  

Join Dr Sarah Mizielinska as she speaks with Professor Chris Shaw, whose experience as a clinician and medical doctor has driven his scientific research. His work focuses on gene discoveries in a hereditary form of motor neuron disease (MND) and how to translate that knowledge into developing treatments for neurodegenerative conditions such as MNDand frontotemporal dementia (FTD). Hear more on the latest cutting-edge research happening at the UK DRI, from understanding how molecules move around cells to developing new gene therapies.  

Whether you're living with one of these conditions, are a carer, researcher, or simply curious about neuroscience, this conversation provides insights into these complex conditions and hope for new treatments on the horizon.  

Episode 3 definitions

Progranulin

Progranulin is a secreted, multifunctional protein encoded by the GRN gene. Loss-of-function mutations in the Progranulin gene are a major cause of frontotemporal dementia.

Glial Cells

Glial cells or glia are non-neuronal cells in the brain and spinal cord. They provide structural support, insulation, immune defence, and nutrients/oxygen for neurons.

Chromosome 

A chromosome is a package of DNA containing part or all of the genetic material of an organism. Humans have 23 pairs of chromosomes containing all our genetic information.

Mutation

Mutations in the context of neurodegeneration refer to changes in the DNA that can affect how a protein is made, where in the cell it is located or how it behaves. In neurodegenerative conditions mutations often lead to protein accumulation or loss of function.

Genetic risk factor

Genetic risk factors are inherited variations or mutations in DNA that increase a person's risk of developing a disease. These factors are often identified through family history, and they are not a guarantee that a person will get sick. Environmental factors also play a key role.

Pathology

Pathology is the study of disease. In the context of research, it can also refer to the typical manifestation of an illness. For example, the pathology of frontotemporal dementia includes the shrinking of specific brain regions (frontal and temporal lobe).

Therapeutics

The word therapeutic(s) refers to a treatment, therapy or drug in the context of disease research. In this episode the therapeutic discussed is the delivery of a missing protein to the brain with the help of a virus.

For more detailed information about any of the conditions mentioned, visit:  

Frontotemporal dementia: https://www.ukdri.ac.uk/conditions/frontotemporal-dementia 

Motor neuron disease: https://www.ukdri.ac.uk/conditions/m

Learn more:  

📚 UK DRI website: www.ukdri.ac.uk 

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

📧 Newsletter: tinyurl.com/ukdri-newsletter  

Find us on: bsky, LinkedIn and YouTube

Transcript

SPEAKER_00 0:00

Welcome to Between the Signals, a podcast brought to you by the UK Dementia Research Institute at King's College London. As our population gets older, dementia has become a major health challenge. If nothing changes, half of us could be affected by dementia in some way. Either facing it ourselves, caring for a loved one, or both. What is a neurodegenerative condition? How might these conditions affect us and our future as we age? These are exactly the kinds of topics that we're breaking down on this podcast. And we hope you enjoy it.

SPEAKER_01 0:45

My name is Dr. Sarah Mazalinska, and I am a group leader and the UK Dementia Research Institute. And today we have the enormous pleasure of having Professor Chris Shaw here with us to talk about his experiences, his amazing discoveries in the genetics of both motor neuron disease called M and D, but also known as amiotrophical Lateral Sclerosis, ALS, and also how he's taken these discoveries through to have a spin-out company of his own and actually take uh get therapeutics to people affected by neurodegenerative conditions. So welcome, Chris. Great to have you.

SPEAKER_02 1:23

Nice to see you. Thanks, Sarah.

SPEAKER_01 1:25

And so we want to take you right back to the beginning and how you came into research and how this journey began.

SPEAKER_02 1:32

Right. Well, I should start uh in New Zealand because that's where I'm from. I trained in medicine and I wanted to become a hospital doctor, a clinician, a physician. And so I'd do a variety of different subspecialties, but neurology for me was the most challenging. There were no treatments for most conditions. We didn't really understand what was going on in the brain. In New Zealand at that time, we didn't even have MRI scanners, right? So it seemed to me to be the area in which there was the greatest need for improvement in advances. And I started doing some, you know, sort of research in the weekends and at nights on a condition called multiple sclerosis, which is an inflammatory condition of the brain, and we were looking at how the inflammatory system was being switched on in this condition. And I managed to write some papers and got a Wellcome Trust Fellowship to come to Cambridge in the UK. And for me that was transformative. But my first encounter with people with motor urine disease was in New Zealand, and it was very depressing because obviously you're giving people a terminal diagnosis, and we knew that the disease was was progressing pretty fast. But most people don't know what's coming. There was very little known about motor urine disease. But when I came to the United Kingdom and I was working in a small clinic, I met my first patients who had a familial form of it. That is that they'd inherit it from a parent, and they knew exactly what was coming. And talking to them and hearing about the burden that they'd carried all their lives, every time they tripped on a pavement or had difficulty opening a door, they thought this was the beginning of the disease. Not only that, there were two women in their 50s, and they knew that if they carried the gene, that they would have then had the chance to pass it on to their children. And that's the sort of, you know, the impact of that on them really changed my focus to then spend the rest of my life trying to work on understanding this disease process and develop some therapies.

SPEAKER_01 3:28

You started understanding the these familial cases. So where did that take you to in your research, Jenny? What did you come to Cambridge to do?

SPEAKER_02 3:36

Yeah, so so I I went to Cambridge to sort of look at how nerve cells interact to be able to help the brain recover from multiple sclerosis. But I learned a lot about how nerve cells and the supporting glial cells uh you know work in systems. We were able to grow them, we were able to look at um the impact of various genes. Um but it was this this uh familial motor neuron disease that really attracted my attention about going forward because um at the that stage the first gene was discovered. It was called SOD1. Okay. And indeed, both these women carried SOLD1 mutations. Right. And that led to me to work with uh somebody at King's called Professor Nigel Lee, who was an international expert in this area, and he helped us identify these gene mutations, and then we started to study the disease process in these people. So that's how I got started. Um he offered me a job at King's and I've been here for 30 years.

SPEAKER_01 4:32

So, yes, you have, I mean, been instrumental in the discovery of many genes and genetic risk factors for motor neuron disease. And can you tell us a little bit about how that process, how do you how did how does that occur? How do you find these genetic risk factors?

SPEAKER_02 4:46

Well, it was extremely difficult. I was employed between the neurology department and the genetics department, and the professor of genetics said, Oh, motor neuron disease, that's not genetic. Anyway, it's because very few people can perceived it to be genetic. And the other challenge was in traditional genetic linkage studies, you you tried to discover a gene that was running through multiple generations in very large families. In most neuron disease, everybody who's had the disease in previous generations is dead, right? And so we had to try and recreate missing people from these families by genotyping the spouse and the children and to see what genes the missing spouse would have had. And that's a very slow and difficult process. So it was a pretty imprecise science, which took us a long time to discover more genes. And the first really big gene, an important gene that we discovered was TDB43.

SPEAKER_01 5:35

You mentioned genotyping. So, how what's the link between genotyping and genetics?

SPEAKER_02 5:40

So most people know about DNA and sequencing. So there are various signals that we can see tracking along different chromosomes. And the way we genotype people to do linkage is to see which, if you like, markers people are carrying in their different chromosomes. And we can track down which chromosomes are being shared amongst all the people that carry the disease and not shared on those who aren't affected.

SPEAKER_01 6:01

And so, with all these genetic understandings, how do these help tell us about the kind of biological underpinnings of these conditions?

SPEAKER_02 6:08

Well, it's really interesting. So many of these genes actually uh lead to defects in the same part of the cellular machinery. Right. And a particularly important part that I'd like to focus on is the protein recycling machinery. That seems to be hit by a number of different genes which all can all cause motor neuron disease or frontogembal dementia.

SPEAKER_01 6:28

So you mentioned frontogemboral dementia kind of in line with motor neuron disease. Why do you mention these two together?

SPEAKER_02 6:34

Well, um, they seem to be related both in terms of uh the genetics but also in terms of their pathology. So we know that when we look into the brains and spinal cords of these patients, the same sorts of proteins and the same sorts of genes are being affected. So we now think of them as being a spectrum of disease. And some people have more frontogenementia where the uh frontal lobes and the temporal lobes take the burden of disease, and other people, sometimes even in the same family, it's the spinal motor neurons that are most affected.

SPEAKER_01 7:04

And so can can uh single individuals have both of these diseases?

SPEAKER_02 7:10

Some very unfortunate people will be affected by both conditions, neither of which are great.

SPEAKER_01 7:15

But it's also then understanding the genetics and developing therapeutics for these means that we could develop therapeutics for both, right?

SPEAKER_02 7:24

That's a really exciting opportunity. That this isn't just going to be about one single gene in one small population of patients, but we could generalize that across that. And TDP483 is very interesting because we know it's it's important for frontothermal dementia, motor urine disease, but about 40% of people with Alzheimer's disease and Parkinson's also have TDB43 accumulating, and we know in those individuals it's also contributing to disease and symptoms.

SPEAKER_01 7:49

So, speaking about therapeutics, not only are you a clinician and a researcher and both very successful ones, you're also now an entrepreneur and have your own spin-out company, Aviado Bio, developing and testing um gene therapies for neurodegenerative conditions.

SPEAKER_02 8:07

I don't think of myself as an entrepreneur really. I think of myself as a monopreneur. This is the only company I've wanted to spin out, and I'm not sure I even wanted to. It was kind of an accidental uh event. Um yes, so I've been working on discovering diseases and mechanisms for a very long time. We generated a lot of different discoveries. We generated cells and mice that carried these genes that people were using around the world. We made that available to everybody. Um, but actually the therapies weren't coming through. There was very little progress. And so we decided to do this ourselves. I was very fortunate in working with um some people who'd had the experience of gene therapy before, and together we uh formed the spin-out company. So I wouldn't say it was my motivation, but in the end we felt it wasn't just that we should go on making more discoveries about an explanation about disease mechanisms, we should actually try and develop some therapies.

SPEAKER_01 9:01

So, and how has that been then? How how has that journey to really developing a successful company been?

SPEAKER_02 9:09

So the most important thing is to work with people who have that expertise. And um, so I was extremely fortunate in being able to recruit really good people who had experience and who are able to develop uh therapies and bring them to the clinic. Uh and so the success is theirs, uh, you know, much more than mine. Um so we started off with a therapy for frontal temperature dementia due to progranulin, uh, and we went about it in a in a different way from what most other people were doing.

SPEAKER_01 9:38

Okay, and how you mentioned it's different. So, how is it different?

SPEAKER_02 9:41

Well, uh there's something special about uh progranulin. Uh this mute these patients who have mutations have a deficient in progranulin. And so because they don't have enough progranulin, the cells that are involved in the protein recycling tend to fail. And the the the the cell the mechanism within those cells starts to fail and those uh cells degenerate. Uh and so the idea was that we would give progranulin back. And the reason that we chose progranulin is we knew that it was secreted. And so that if we get into part of the brain and get it delivered around the brain, then we might be able to have a therapy for all the whole brain.

SPEAKER_01 10:16

So is that why you chose progranulin over other ones that you've mentioned, like SOD1 and TB43, these other genes that kind of play a major role?

SPEAKER_02 10:24

So the first thing was that it was a supplement, and that's easier to do than silencing these genes. Uh and the fact that it's secreted means you could go from one cell to another.

SPEAKER_01 10:33

Okay, and so let's follow up on that. So one cell to another. So what are we talking about here?

SPEAKER_02 10:38

So we wanted to make this um the best distributed protein in the brain. And so we looked at a part of the brain that was best connected to other parts, and we chose the thalamus, which is this small structure in the center of the brain, uh, which takes sensory information from the rest of the body and uh delivers that information to the brain in the cortex. And so we asked the thalamus to be the factory to make the progranulin, and we asked it to then distribute it along axons, right, and then uh have it secreted at synapses and being then taken up by other cells in the cortex, and much to our surprise, um, this did actually work firstly in mice and then in sheep and then in monkeys.

SPEAKER_01 11:17

Okay, so I'm just gonna clarify for the audience that um brain cells, nerve cells, neurons is all the same word for the same thing. They have these projections that we describe a bit like a tree, the the branches of a tree. And some of these, um some of these are axons, and these are long projections that connect one cell to another cell. And at the end of these is a synapse, and that really is the connection between two cells. So Chris is talking about his therapeutic traveling along um from one cell and being transported across the synapse to another cell and therefore being distributed through the nervous system, right? Correct. And so what type of therapeutics are these, Chris? Like how are we supplementing this progranulin?

SPEAKER_02 12:00

Well, the way we would deliver the gene was to package it in a virus.

SPEAKER_01 12:03

Oh.

SPEAKER_02 12:04

Which sounds rather scary. Um, but actually, what we're asking the virus to do is just deliver our gene. Normally viruses have their own genes so they can replicate and cause infection. You know, that's what they're out there to do. What we're using is the shell of the virus, and we're putting inside the gene that we want expressed, not the viral genes.

SPEAKER_01 12:22

And so are there no dangers of using a virus like this?

SPEAKER_02 12:26

Yeah, so this is a very small virus. People do get exposed to this virus, but it doesn't really cause any systemic illness, so that people don't get sick with this virus. Right. Okay. And we know it's been given to thousands of people uh quite safely. Um, you know, i we have to worry about dose and all the sorts of other things, but actually it's a pretty safe sort of um vehicle to deliver the genes to the right cells and do the right thing.

SPEAKER_01 12:49

And so what's the benefit of having like a viral uh delivery uh or a genetic delivery of a therapeutic versus having the traditional kind of small molecule chemicals that are, you know, like paracetamal and things?

SPEAKER_02 13:02

Yeah. So a lot of drugs um don't get into the brain.

SPEAKER_01 13:06

Right.

SPEAKER_02 13:06

Uh the brain has a barrier, so things in the bloodstream don't get across, and that's a good idea because you don't want most viruses and bacteria getting into the brain. It's a very delicate organ. Um so small some small molecules do get across the blood-brain barrier, uh, but actually it it's it's they have an effect on every single cell. Um, the nice thing about using a virus to deliver your gene is you can put that gene under certain regulatory control. So it's only switched on in certain sorts of cells or in certain sorts of conditions. Right.

SPEAKER_01 13:36

And so I think you mentioned before as as well as having those regulatory image uh elements that you also directly inject that into the brains of people. Is that what we're talking about here? It is, it is.

SPEAKER_02 13:47

And again, that sounds quite scary. You know, we're going to inject a virus into your brain to give you a gene that you're missing. Um but actually that has been done in other conditions and been shown to be very safe. The part of the brain we're going to, you know, is is regularly uh uh the site for um the delivery of a probe to treat tremor and Parkinson's disease. We use deep brain stimulation. Uh, and this is just a virus that we we infuse into that brain, we take the catheter out, you know, and you're left with the virus in the brain. Um we know uh from our animal studies that actually it's a pretty safe thing to do, and you get long-term expression in the nerve cells. And the nice thing about that is that one treatment could be a treatment for life.

SPEAKER_01 14:28

Right.

SPEAKER_02 14:29

Because the gene keeps being expressed over time.

SPEAKER_01 14:31

Okay, so that's really beneficial either having to keep taking uh a medicine over and over and again.

SPEAKER_02 14:37

So one-time therapy.

SPEAKER_01 14:38

And so it sounds like that's quite a specialist kind of uh procedure. So this is not something you're gonna go to your GP for, is it?

SPEAKER_02 14:46

No, and and you know, that that's a challenge. Um we've gone to centers in the world that are experienced in delivering gene therapies to the brain. Uh, it has to be done in under an MRI scanner so we know exactly where the infusion's going, and we can see if there are any problems during the surgery. So the first phase one and two study is all about safety. Can we do this safely? And then we can answer are we actually getting a therapy made in the person? And then the third question is is it effective in treating symptoms?

SPEAKER_01 15:19

You've made incredible progress in your company taking a gene therapy into humans last year, beginning last year. And so how does that feel?

SPEAKER_02 15:29

Uh scary at first. Um but we're now onto our third cohort of patients. So we're pretty confident about the safety of the procedure. And now we're trying to see a signal as to whether we've actually delivered what we thought we were delivering and and whether uh subsequently we'll find out whether uh it it's been effective in terms of reversing uh the disease process or or slowing down progression.

SPEAKER_01 15:49

And so we've talked about um your incredible efforts targeting progranulin. But so what about the other causes that we talked about before, TP43 and SOD and other ones? Like where is where are we as a field in your company progressing, targeting those things?

SPEAKER_02 16:06

So we chose progranulin because it was secreted, right? Yes. But it's actually a very small number of people who carry these mutations that would benefit from that particular therapy in the first instance. Or many of the other genes that cause uh frontotypementia and motor neuron disease, actually, it's a toxic protein that's being made. Right. Right? So you need to switch that gene off. Yeah. That's much more difficult. Okay. And you need then to deliver your therapy to every single cell you want to save. Right. So rather than asking the factory at the center of the brain to go and distribute it, we now have to get our virus all around the brain, and that is difficult. What I would say is that there are advances in terms of the virus capsule that are being made so that it can get across the blood brain barrier. And so that's a really exciting development because if we can get it across the blood brain barrier safely, then we could get it to deliver almost every single cell in the brain. And indeed, there are now capsids out there that are doing that, and we are working with them.

SPEAKER_01 17:04

So we've talked about targeting these toxic proteins, so um, from these genetics that we mentioned earlier, like TDP43 and SOD1. Do we need to target all of these different genetics? Is that the plan? Like we go after all of these genetic, big genetic factors that so that would be pretty challenging.

SPEAKER_02 17:21

Um, and I I think um there may be individual strategies, but what I have been focusing on uh with in the company is to look at uh where they come together. I I kind of think of this as like different tributaries to a mainstream. Okay. And rather than tackling every single tributary individually, I'm going to look at the pathways that the where they come together, in particular around TDB43 um uh uh protein accumulation. And and I think we have got some important genetic clues there as well. And and if you can dam that river, then perhaps you can delay or slow or even arrest the disease process downstream.

SPEAKER_01 17:56

So do you think we'll is it better to target downstream, or do we need to target upstream as well, or what are we talking about here?

SPEAKER_02 18:04

I think a bit of both. We talk about um perhaps combination therapies in the future. Uh and so there may be targets that are for an individual with a particular gene variant, you might target some element there, but you also want to target the mainstream as well. And it won't just be gene therapy, there'll be other small molecules that are make a contribution, you know, and and this is just one particular approach that we're we're tackling.

SPEAKER_01 18:24

So it sounds like we're making amazing advances in gene therapies and targeting genetics and downstream kind of these places, as you say, that fill into this stream. So, what's your future perspective on how are we going to where are we going to make the best impact to people with these conditions?

SPEAKER_02 18:41

Okay, so I think if we can show that these gene therapies are effective, that's a great start. Um but one of the problems with a one-time therapy is you can't change the dose.

SPEAKER_01 18:50

Right.

SPEAKER_02 18:51

And so, you know, that's the dose you're gonna get for the rest of your life. Um, what we are looking at now is ways of tuning that therapy so we can turn it up or turn it down. And there are small molecules that cross into the brain that are able to trigger um the therapies. The other thing to think about would be could we put inside our therapy a trigger when that cell becomes sick?

SPEAKER_01 19:16

Right.

SPEAKER_02 19:17

So it's able to detect a change in the cell's uh biology that suggests it's beginning to struggle, and you switch on your therapy in those cells. And then we really could treat people who are at risk who carry these genes who are not affected, and the therapy will only uh start up in the tissues that are really being affected at the time they need it.

SPEAKER_01 19:36

So this is not just about making more therapeutics, it's also making our therapeutics smarter as well. Exactly. Yes. And so how do people with these neurodegenerative conditions feed into this research? Like what role do they play in the development of these therapies? Aaron Ross Powell, Jr.

SPEAKER_02 19:51

So they're at every single stage of the process. You know, the reason I started working in this area was because the need was so great and these people were facing a really bleak future. Um, and although they knew that I was really unlikely to better help them personally, what we were hoping to do is to change our understanding of disease and develop therapies that would help their children. And we're still doing that. And obviously, I've been doing this a long time. So I'm now seeing the children to come through. And sometimes we do have a therapy that really has changed the options going forward. And I think for SOB1, that's definitely true. There's a therapy that really can work and is very powerful. Uh, but for the majority of people, we're still waiting for that next breakthrough.

SPEAKER_01 20:34

But there is hope.

SPEAKER_02 20:35

There is hope, and we now have the tools to to really tackle these in a serious fashion in a major way.

SPEAKER_01 20:42

And you've made an enormous contribution to this, Chris, over your career.

SPEAKER_02 20:45

That's very kind, but um yeah, it's a huge team effort. I mean, the company is now 60 people, all experts in gene therapy. I I I just lit the fire. They've been fueling it.

SPEAKER_01 20:56

It's always a team effort in science, right?

SPEAKER_02 20:58

Yeah, always.

SPEAKER_01 20:58

Always. Thank you so much, Chris, for coming here today and sharing uh really how you got into research, you know, your discovery of so many genes across uh motor neuron disease and also other diseases, and then really taking these kind of fundamental discoveries all the way through to developing treatments and really kind of um bringing those to people with neurogenerative conditions. Thank you so much.

SPEAKER_02 21:25

Pleasure