Episode 6: Gene Therapy
Welcome
This episode hosted by Olivia Moir, dives into the field of Gene Therapy with guest Professor Simon Waddington. We discuss what gene therapy really is, and the different methods used, as well as the goals of gene therapy. This field is one with many different misconceptions, which we address on the episode. In addition to this, there are a number of different applications of gene therapy, which we discuss, and how gene therapy is being used today.
About the Guest
He has contributed in many ways to science commumication, namely through the charity “Medical Aid Films” he co-founded in 2006. This is dedicated to help medical training and education in low income countries using a multimedia approach - check it out here: www.medicalaidfilms.org
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Transcript
Speakers:
Host - Olivia
Guest – Prof Simon Waddington
00:00:04 Olivia Moir
Hello, everyone. Welcome back to it all starts here. This is a podcast focusing on the communication and education of topics in reproductive science and Women's Health. I am your host, Olivia Moir, and we are here today at the Institute For Women's Health at UCL here in London. And today I am extremely excited because we are going to be taking a bit of an adventure down the genetics lane. My personal favorite lane to talk about gene therapy. So to do this, I have with me the wonderful professor Simon Waddington, who is a professor and researcher in the field of gene therapy here at UCL, he currently leads a team developing translational gene therapy for childhood inherited genetic diseases, including neurodegenerative diseases, inherited epilepsy and metabolic diseases. And on top of this, he chairs the cell and gene therapy therapeutic innovation network of the UCL Translational Research Office. He has been working in this field for over 20 years and alongside his team has published more than 160 papers in peer reviewed journals including Nature, Cell Science, Translational Medicine and many others. So I am beyond excited to have you here and to be speaking with you today about gene therapy.
00:01:39 Olivia Moir
So I think let's just to start it off, maybe we can talk a little bit or you can talk a little bit about where this kind of started for you your journey?
00:01:46 Professor Simon Waddington
So so actually I I grew up in a in a household which was quite engineering and science focused. So I mean, although my mom was not employed as a scientist, she certainly believed in conventional, scientific and and medicinal approaches to things.
00:02:06 Professor Simon Waddington
My dad was an engineer, mechanical engineer and my brother is or was an electronics engineer. So we had quite a lot of science books around the place, so I would read these books and I I knew that. I just. I just loved science when I was, you know, eight or nine years old. I didn't really know which science I would want to do for my for my career. You know, I thought of maybe kind of, you know, being a a rocket scientist or maybe being a doctor, but it was actually it was biology that really, really intrigued me. I think more than anything else, you know, I've got, I've got an image of a book that I was reading where it was describing Alexander Fleming and the penicillin and this sort of stuff. So I think this really caught my imagination, which is why so. So when I was doing my A levels, I decided to do biology, chemistry and maths.
00:03:07 Professor Simon Waddington
And my dad said, why are you not, Why you not doing physics? Because you're good at physics. And I said because I I love biology. And he said, well, there's there's no career in biology. And I said, yeah, but I I want to do what I what I love doing.
00:03:18 Professor Simon Waddington
So that's where it all started off.
00:03:20 Olivia Moir
That's amazing. Yeah, I feel like it all kind of, not all the time, I mean, for me, I definitely didn't start with a passion for science, but I think, you know, it's really cool when it kind of comes out of that at some point. I think it always does come out of a a passion and an interest and and that's where the most successful stories maybe come from.
00:03:41 Olivia Moir
So kind of turning into like gene therapy where I guess that's been, you know, a long course of study and research for you. How did that, you know, how did you go from biology then to genetics then to specifically focusing on gene therapy?
00:03:57 Professor Simon Waddington
So I I came out of my first degree at the University of York and actually and and still it was then. Not sure what I wanted to do. I was quite interested in computers. So I did a degree in biological computation, so this was back in 92 when computers really were not that fancy. Pre Internet days really. And so I I was unsure and I didn't really understand the sort of jobs that I could get so literally, It was just a scattering approach looking at the back of the jobs that were advertised in New Scientist magazine and I applied applied for, I don't know, 30-40 jobs. With little success. And then at the same time, I was offered a job in Cumbria to do analysis of Fern databases. And I was offered a job down in Googe street, down here in London, to do editing of journals and I was also offered a position at Saint Mary's Hospital Medical School where, of course, Alexander Fleming was based to do a research position in kidney disease. Well, actually so that was the one that grabbed me. The one to do with research and kidney disease. Even then, I didn't really understand what it meant to do a PhD so my my line manager, my supervisor, her name is Vicky Cattel. She was a histopathologist. And and the and. And actually she's one of my great inspirations because she taught me a huge amount of what I know about scientific method, about rigorous experimentation, about writing, about presenting.
00:05:48 Professor Simon Waddington
And so I was down at Saint Mary's. So quite a long while actually, because it was a part time PhD. I was down there from 93 to 99. And during that time I uh became friends with one of the departments below in the same building. That was the gene therapy. And so I became good buddies with these people who used to go down the bar and hang out, hang out and play football with these, these people. And it just happened that they had a job going. Uh, as I was finishing up at A at a with Vicky and St. Mary's in gene therapy. So I'd I'd kind of at that point, been working, you know, doing stuff with them, doing, you know, doing experiments with them helping. But this is when I leaped into it was in 1999, and unfortunately at that point, gene therapy was just about to go into a little bit of a of a crisis, probably the biggest crisis in in in gene therapy. I was oblivious to this because I haven't really experienced the the high side of the. Through the 90s, so I kind of I I arrived at a fairly low point where I think there's I think maybe the bar was quite low at that point and but what it did mean is that I was able to to to become established.
00:07:10 Professor Simon Waddington
So I then so it was the the group of Professor Charles Kittel. And he actually, he gave me a lot of the leeway to be able to, to direct my my interests and, you know, develop my research passion in, in gene therapy. So, this is what the crucial part is, That I think, yeah.
00:07:28 Olivia Moir
I love that I love how go with the flow it was and Kind of Maybe. Yeah. Unplanned you just kinda.
00:07:37 Professor Simon Waddington
Yeah. If if I have, if I, Being a person applying to me now, I would have said I'm sorry, but you have no focus. You you you don't know what you want to do. You clearly aren't interested in this. So I think this actually I don't. I don't give myself a stern talking to yes. Yeah, yeah.
00:07:50 Olivia Moir
OK, interesting. So thinking a little bit about gene therapy and maybe trying to explain it to everyone listening, if you were, I mean, we've talked a little bit about the fact that it's just really actually such a broad topic. I mean, when you think about it, it seems like a little niche, which of course it is. I think that's, you know, obviously the great thing about genetics is there are so many incredibly cool niches to study and they're all very kind of complex in their own way. But also they have just so broad. So in gene therapy, if you were going to explain that, how would you kind Of go about that?
00:08:33 Professor Simon Waddington
So I think the first thing that it's important to note is that gene therapy spans a lot of different disciplines to treat a wide range of diseases. So gene therapy encompasses a huge range of different tools that are there to manipulate genetic material of cells, DNA and RNA. So at at the end of the spectrum, furthest away from the work that I do. Are things such as oncolytic viral therapy. So here you're taking a virus, disabling it, and then using this to deliver genes that will kill tumor cells. So when these when these oncolytic viruses are injected into a tumour, they will deliver their toxic payload and also not only will they kill the cells, but they'll also use an immune response against the tumour. That's at the very far end, away from what I do because what I'm, Me and my team and collaborators work on is developing gene therapies for inherited genetic diseases. So these are patients that have got a defective.
00:09:48 Professor Simon Waddington
For example, it might cause cystic fibrosis muscular dystrophy. Earlier and what we are then attempting to do is to stealthily deliver working copies of the gene into the cell without inducing an immune response and to deliver efficiently, hopefully so that a single delivery can last for the lifetime of the individual, that's the aspiration.
00:10:17 Professor Simon Waddington
So then if we just talk about about, why would you do gene there before a rare disease rather than any other treatment. So let's take hemophilia. It's a great example is this. So hemophiliacs they it before around 1985. The way to treat hemophilia is that they would receive concentrated plasma from from non affected individuals and this plasma would contain the coagulation factors that they're missing. So it meant that they had to inject themselves, or maybe would be injected with large volumes of this plasma, even though it's concentrated. And unfortunately the hemophilia community was beset by the fact that these the blood was contaminated with hepatitis and HIV after about 1985, there was the advent of recombinant protein production, so therefore growing proteins in VATS, bioreactors. And so it was possible, for example, to to grow one of these clotting factors in a bioreactor, make its highly concentrated, and then hemophiliacs could inject themselves with that. And this was quite transformative to the gene theorem community. It meant that they would have to inject themselves two or three times a week. For their whole life and and and when they inject themselves, the protein the protein would would go into the circulation. Unfortunately, it would only stick around for a half life of by 18 hours and then it would go away. So what it means is that they essentially had peaks and troughs of of of of therapy for their hemophilia. So hemophiliacs, they bleed one of the main problems is that hemophiliacs they bleed into their joints. And so they ultimately develop serious arthritis.
00:12:09 Professor Simon Waddington
So even though they were receiving this amazing therapy because it was repeated injections, it it didn't cure them and they could still develop the joint bleeds. Moreover, it was incredibly expensive about £100,000 per patient per year. And of course, the burden of them having to inject themselves with the clotting fighters.
00:12:32 Professor Simon Waddington
Now, over the past couple of years have been the licensed market approved gene therapies for hemophilia SA&B. This is certainly for hemophilia B. This is a single injection that as yet is is lasting the patient were 10 years. So although we rarely want to talk about a cure in gene therapy. It means that they have not had to inject some of these patients have not had to inject themselves with any factor for 10 years. And 10 years and going. So this is the transformation, is that rather than having to take a drug or a medicine every day, every other day, in theory, with the gene therapy, it's one shot and you're done.
00:13:24 Olivia Moir
Wow. That's amazing. And so. OK, so one thing that kind of became clear to us in my you know in my background is in genetics. I did my undergrad in that. And one thing that people were talking a lot about towards the end of it is about like the variability in genomic sequences between, you know, different sexes between different, you know, ethnicities, people from different areas of the world in the context of gene therapy. I'm assuming that there is like, maybe a reference genome that you would use or sort of use during your development of a therapy, like how does tha work?
00:14:01 Professor Simon Waddington
Yeah. So I mean, certainly gene therapy has has been progressing through the low hanging fruit of diseases where these are in theory diseases that should be easily treated by delivering a working copy of the gene.
00:14:15 Olivia Moir
Right.
00:14:15 Professor Simon Waddington
So. So there hasn't been a huge amount of attention paid to uh, the nuances of the sequences and so. So the way we've tended to do it is that we just go to the reference reference database. Yeah, online, get a sequence from the, from the unaffected reference genome, and then use this, insert it into the vector and then delivering it into the cells into the mouse models or into. Then ultimately the patients.
00:14:45 Professor Simon Waddington
It clearly isn't quite as simple as that, because we make different versions of the gene in in, in different cells in our body, and indeed, as you say, is that different individuals will express slightly different versions of the gene, some will work better, some will work less well.
00:15:06 Professor Simon Waddington
And so I think there's now, you know, there is some work going on to try to choose the best possible. version of the gene, but it it's still gene type is a really you know it's quite a blunt tool. All you're doing is there's. There's the. The gene is not working. So therefore you're putting in extra copies, hoping that they will supplement. Or now there is a move to treat diseases which are dominant, so therefore you have to knock down a gene as well as maybe knocking a gene so things are getting. But thankfully the technology is is has improved so much now that we're able to consider these nuances and and and have more complex solutions than we ever ever really dared, that we might be able to to to think about, yeah.
00:16:01 Olivia Moir
That's interesting. So you, I just caught what you said earlier is that in the community of gene therapy, there's like a resistance around saying a cure for something. I feel like I have an idea of why that is, but maybe you could explain.
00:16:20 Professor Simon Waddington
For example, one of one of the most stunning examples of gene therapy clinical success, I think with spinal muscular atrophy, type 1, spinal muscular atrophy. These infants are untreated by the age of two, they would be uh. It's a neurological neuromuscular disease. So by the age of two, they would have there's a gastric tubes. They would be under, uh, positive respiration because they don't have the muscle strength to be able to breathe or swallow. Uh. And without those, uh, 90% of them will not live beyond their 2nd birthday. So there was a gene that we developed and delivered the survival motor neuron protein gene to these infants, so it's a single injection as early as possible because it is more effective than earlier that you go, and and these infants are now running around at five years of age. Walking, talking. Some of them are difficult to distinguish from unaffected children. But they aren't completely cured. They still show some aspects of the disease. They do have some evidence of neurological deficits and moreover, it's really early because you know, these are these are this is the first cohort of patients that have ever been injected.On maths with these gene therapy vectors, so we might find out that in 10 years time there's an aspect of the disease that we didn't appreciate. And the reason that we didn't appreciate it is because no kids ever live until the age to see that. So we're starting to by treating some aspects of the disease we might be starting to uncover other aspects that we never truly understood or were aware of.
00:18:23 Olivia Moir
Interesting. So it's kind of an ongoing process. You're kind of, and we're all just, Still figuring it out, I think is the biggest thing about science is that, you know, they're the we're trying our best but it's a constant learning process for everyone involved.
00:18:39 Professor Simon Waddington
There's never a point when we go: Yes, OK, we're done. It’s not never happening.
00:18:47 Olivia Moir
True. OK. So in the field of gene therapy, I mean maybe separate from a dinner party with your parents and your brother because these people sound like the kinds that would completely understand everything that you have to say. But maybe people that you're at a dinner party with your friends that aren't so familiar with the fields of science, do you find that there are common questions that people have, or maybe even like misconceptions you know? What's something that people are constantly flocking towards you about with gene therapy and you're like, I wish that I could address this or this is so kind of misunderstood. Are there areas of the field where you're like, I wish that, you know, people might just see it from this perspective instead?
00:19:36 Professor Simon Waddington
There are a lot of questions that people ask. One of the one of the things that people I think struggle to get their head around is that it is in theory just one injection, and then you're done. And the question then is, will it really last forever? We don't know that. The principle of it is that you should have one injection, that you're done.
00:20:13 Professor Simon Waddington
I think one of the other questions is around the fact that the most effective gene therapies. Use vectors that have been derived from human viruses. So one of the vectors is based upon HIV. Another vector is based upon adenovirus, another vector, is based on what's called AAV. And so, you know, people are thinking, well, you're injecting people with viruses here. Surely this is a bad thing. We're not because the the technology is such that you've stripped out all of the all of the virus genetic material and are just putting in the genetic material that you want to deliver. So a gene therapy vector is is about as similar to a virus as someone wearing a leather jacket is to a cow. The contents are entirely different. So I think you know, I think that's one of the things that.
00:21:21 Professor Simon Waddington
Needs disambiguating, I think.
00:21:23 Olivia Moir
Yeah, I think that's important. And I think particularly in the reason I ask is just because I think particularly in the field of genetics and also you know, the idea of a therapy. So an injection, I think with COVID, people became a lot more kind of aware and wanted to educate themselves on these kinds of topics, but there's also just so much misinformation out there and a lot of different kind of theories about what certain things could be, and I think it's important to kind of address them and talk about them and you know open that conversation up a little bit as to what the reality is.
00:22:04 Professor Simon Waddington
It's it's funny actually, because so you know there there are I think there there are two major genetic vaccines there was the there were the RNA vaccines, and then there was the adenovirus vaccines. And you know, for for those of us who have worked in adenovirus gene therapy at one point or another. We've always had to to to be very diligent about filling out the safety forms in case we ever inject ourselves with an adenovirus and a lot, and we are in the field aware that if you inject yourself with adenovirus, you aren't going to come to much harm. But there were always reams of forms. And and it was always kind of with a, a wry smile that we then realized when the adenovirus vaccine virus was rolled out. When all of a sudden you were getting hundreds of millions of people injected in the arm with an adenovirus that we would otherwise have had to fill our state for you know Ithink that the coronavirus vaccines are are an interesting example. Because for some of the adenovirus vaccines they clearly caused some side effects. So they they caused micro thrombosis. So I think that you know it's it's an important consideration that all treatments, it's a risk benefit analysis. There are going to be some risks and of course there gonna be some tremendous benefits. It's the same with it's it's not this isn't just gene therapy we're talking here about you know paracetamol. I mean, paracetamol actually is one of the most dangerous drugs there are. You know, there are a lot of hospitalizations for people taking paracetamol. The side effects are quite serious. So, you know, I think that it's it's important to remember in medicine that that, that there isn't, there's rarely ever a truly, completely and utterly benign medicine. It's going to have some side effects in some people and so, so we have to always balance this risk benefit analysis. Yeah, when we're looking at developing these treatments, I mean for the kids with type 1 spinal muscular atrophy, they're not gonna, they're not going to see the the 3rd or 4th birthday. So. So therefore, you know, injecting them with something, you know, huge amounts of of of gene type of vector, you know in, in in 10-20 years time this might cause problems, but at least they're going to be able to see there, you know early years, for example.
00:24:41 Olivia Moir
Absolutely.
00:24:56 Olivia Moir
Thinking a little bit about like sort of the communication of this topic like gene therapy, I think you know, you mentioned to me before you've done different you know conferences and and bits with certain. Like panels or whatever that you where you've educated all on the topic of gene therapy, but you kind of mentioned that sometimes and of course you know like as we said it's it's a broad topic but thinking about like communicating on this, do you think it's important to talk about gene therapy in a more kind of casual way like do you think it would be helpful or or beneficial to that this field that if people knew more about it.
00:25:22 Professor Simon Waddington
Absolutely. So. So the so. So I was involved fair, fairly fairly early on in the activities of the British Society for Gene Therapy and one of the mainstays of the activity of the society was to try to educate the lay public and schools to try to explain what gene therapy was, what cell therapy was as well, eventually, and to try to demystify it and to also to to try to place it in the context of reality, so therefore since 2006 there have been an annual public engagement day with every BSGT meeting. So absolutely, I mean the the field is is, is is very, I mean the field was very aware because in the early 2000s, gene therapy was going through the patch and people thought that it was finished and people didn't realize that actually it was just on the cusp of of of delivering. Mm-hmm. So so I think it's it's really important to be able to communicate this. And I think the BSGT does it really well and I think the European Society now does it really well. And I think the American Society of Gene and cell therapy does it really well as well.
00:26:50 Olivia Moir
Well, that's good. Yeah, that's great. I I definitely think that it's gotten a lot better and I think that, you know, obviously with COVID there was and a ton of, you know, really awful and harmful things. But there were also a lot of helpful things in terms of, like, you know, evolving the Community in terms of science, communication and that kind of the gaps that existed there. But I think Speaking of gaps, do you find? In the research community and the clinical applications of gene therapy, I think it, you know, especially with patient involvement, do you find that there are gaps that exist between kind of like what you're doing in the lab versus what is being practiced or? I just, I feel like there's so much of the time in different fields, like a discrepancy between like the current guidelines around clinical practice and what patients know versus like what researchers are doing and what their passions are. Do you find in gene therapy, there's common things that exist.
00:27:46 Professor Simon Waddington
So I think that that in, in gene therapy it's it's very much being focused towards clinical translation. And I've noticed that you know when people have asked me how do you choose a disease or a project quite often the drivers for this are clinicians that have patients, who, they are frustrated not to be able to treat and therefore want to develop treatments for them, genetic treatments for them, or sometimes you have patient organizations where they've pulled themselves together and and essentially they are calling on the researchers to say, can you can you concentrate on on this area. So we're kind of we're almost you know, we've in in many cases we've been quite often led individuals who have who have got it and that can be both of the clinicians and the patients.
00:28:50 Olivia Moir
I think that's nice. I think that that's like that's how it should work. It would be good if that could work more often in in the different areas of science too, cause I feel like that would close gaps.
00:29:07 Professor Simon Waddington
Yeah. I mean, I think my actually my, my, my criticism, my slight criticism of gene therapy, Is a little bit the opposite in that is that quite often some of the basic science is being kind of almost papered over, kind of. You know, there's a huge amount that we don't know and we I think we would really benefit, we would really improve these. You know these gene therapy vectors by understanding more of the basic science, but but it gene therapy is very much driven driven by translation and and you know and looking at clinical benefit.
00:29:38 Olivia Moir
Which I think is important, you know, in genetics, you know, given the the, the past and history in the field, I think it's probably also one of the reasons that it's so driven by clinical kind of needs. OK. Well, that's, you know you mentioned that kind of just thinking you know, going forwards in your in your future. And your career with gene therapy kind of what are you hoping? Do you have goals that or not specific to you, but just for the field in general that you hope that you'll see like what are your main goals?
00:30:15 Professor Simon Waddington
I think that one of the one of the problems that's facing gene therapy at the moment is that gene therapies are costing a lot of money. And this is causing problems for for the healthcare systems, for the insurers.This not only is causing a problem, but also it's a perception problem as well. So therefore for example, I think it's like it the the hemophilia gene therapy is something like 3,000,000 for one shot. Which is, which seems an incredibly incredible amount, but when you think that it could be a single shot and then you never have to give that path protein therapy anymore and it means that they never have to go into hospital. They're never going to develop the joint blades. If you're looking at the at the outcome of this, I'm not saying 3,000,000 is a is a is a good figure, but certainly you have to take all into consideration. Yeah. So I think I think, but of course this means that that some countries will never be able to afford these gene therapies. So I think that ultimately the prices of these is is going to come down a lot.What I think has happened is that so gene therapy has has now made fantastic inroads into genetic diseases and and I'll bunch Car T cell therapy for treating blood cancers in with this too, there's been some fantastic progress made treating blood cancers that are refractory to other treatment. But these aren't the common diseases, I think. What is happening now is that it's it's almost like we've now got over the foothills. People have become a bit more comfortable with the idea of genetic therapy and what we will then see is the application of genetic therapies to a whole bunch of more common conditions. You know whether they be Asthma. Eczema. Pulmonary fibrosis. Liver disease, what have you. But I think that now the we've got a a huge number more tools for gene therapy. And I think now we have the confidence to start start to look at treating some of the more common conditions as well.
00:32:46 Olivia Moir
Yeah, well, that would be good. I'm I. This has been so great. This conversation, I feel like I've learned so much, and I'm sure everyone listening feels the same way. I'm really looking forward to seeing. Kind of everything that you're going to do and and how the field evolves, but thank you so much.
00:33:03 Professor Simon Waddington
Thank you very much.