Episode Transcript
[00:00:00] Speaker A: Hello and welcome to gosh pods. I'm Dr. Kiki Sirad, the director of Research and innovation at Great Ormond Street Hospital and I'm delighted to be hosting this podcast today. Today we're switching it up a bit as we dive into the fascinating world of the Zeid center for Research into Rare Disease in Children. And I'm joined by none other than Manju Kurian, who I'm going to introduce in just a moment. In this episode, together with Manju, we're going to explore the incredible story behind the ZEID center for Research, which is the world's first purpose built facility focused on pediatric research into rare diseases. Then we'll take a deep dive into neurogenetics where Manju leads a groundbreaking research program investigating childhood neurological disorders. So, Manju, thank you so much for joining us today.
[00:00:52] Speaker B: Thank you for having me.
[00:00:53] Speaker A: Oh, it's so good to see you and to do this episode with you. So for our listeners, I wanted to give an introduction into our guest speaker today. I've known her for a while and she's a leading expert in pediatric neurology and a world renowned clinician scientist. As a professor of neurogenetics at University College London or ucl and also a consultant at Grey Dorman Street Hospital, Professor Kurian has been at the forefront of groundbreaking research in childhood neurogenetic disorders. Her work has changed patient care and also changed our understanding of genetic causes of movement disorders and epilepsy in children. And she's made some incredible discoveries in this area that are opening new doors for treatments. So we're excited to dive into her journey, her research and how she's shaping the future of precision medicine for children with rare diseases. So thank you Manju and I've seen some of the videos and case studies of the children that you've treated and it's quite remarkable what you have achieved.
So before we begin, I thought that what we would do is a bit of scene setting and we can say a little bit about rare diseases and what they mean for children. And then we can also say a little bit about what we're trying to get out of this episode for listeners. So I might start with a few stats and then I'll hand over to you, Manju. I've got some figures here from the UK Rare Disease Framework. Rare conditions, individually quite rare, but collectively they're quite common. And there are over three and a half million people in the UK living with a rare condition. And a rare condition is one that affects fewer than one in 2,000 people, so they're quite rare. And one in 17 people will be affected by a rare condition in their lifetime. So that's quite a few. And many of them, seven in 10 affect children. And more than three out of 10 children, quite sadly, will die before their first birthdays. So, Manju, I don't know if you. Do you want to say anything more about rare diseases, but also what we're trying to achieve in this episode?
[00:03:07] Speaker B: I think you've said it all, Kiki. I think collectively rare diseases are actually common and important. I think they teach us so much about common disease.
Many of the pathways and mechanisms that cause rare disease also cause common disease. And many a time you'll see a treatment for a rare disease that is potentially applicable to more common diseases. And that's particularly true for things like infantile forms of Parkinson's disease that may be relevant for adult Parkinson's disease, treating early neurodevelopmental disorders that may have treatments that are relevant for intellectual disability, autism, and other more common disorders.
And again, it's just very important to think about how all these therapies allow equity of access for patients worldwide.
[00:04:01] Speaker A: I think it's a really good point, as you say, because although you're studying a fairly rare disease, it's very applicable to common disease. And they're a unique system, aren't they? Because often they're caused by one single gene.
[00:04:14] Speaker B: Exactly, exactly.
[00:04:16] Speaker A: So it'd be great now to talk a bit more about you and your background. You graduated from the University of Cambridge and then you trained initially in pediatrics before you decided to sub specialize in pediatric neurology. So I'd love to hear a bit more about your career, your personal journey, and what made you interested in neurological disorders.
[00:04:39] Speaker B: I mean, I remember being in medical school and when I was training in Cambridge, we had quite a long rotation within the neurology department, the adult neurology department. And I just found the constellation of signs and symptoms just such a kind of vocational draw. I can't really describe it better than that, really, that I really wanted to understand more. I mean, the brain is the most fascinating organ in the body, really, in my opinion. And understanding that and understanding how it works normally and understanding how it works in disease, I think is just really fascinating and important. I mean, it causes such morbidity for rare and common diseases worldwide. I think it's important that way. So that was really the start of it. And then after I qualified, I then entered pediatrics. And as part of my pediatric training, I did a very, very Short period at the now Evelina Children's Hospital. At the time, it was guys and working with some very, very talented paediatric neurologists. And kind of it was very clear from there that that's what I wanted to do.
But I guess from there then I decided to train within the field. And I went to Birmingham for some of my specialist pediatric neurology training. And I had this very, very clear memory of sitting in one of my first clinics. I mean, the kind of neuropathology and the kind of the spectrum of patients was just, you know, such an amazing educational tool when I was in Birmingham. But sitting in a clinic with a consultant and I think we saw about 20 different patients and one had a diagnosis and the rest just didn't have any diagnoses. Even though there were many, many things that told us that they had something genetic, something inherited, either they'd be one of a number of siblings that had the same condition, or they had a very progressive condition or a very early onset condition. And all these things really strongly suggested an underlying genetic basis, but that there were no answers for these families, you know, about the underlying cause. And really that's what kind of got me started about kind of, kind of studying genes and the kind of inherent causes for these conditions.
[00:06:55] Speaker A: Oh, it's fascinating. And we know with a lot of these children and their families, they go through, I think it's called a diagnostic odyssey, isn't it? It takes a long time to diagnose them for the reasons that you say.
[00:07:07] Speaker B: Exactly, exactly. I mean, many of the children that I would have seen maybe 10, 15 years ago in clinic, that have had some blood workups, urine tests, a lumbar puncture to take a small amount of fluid from the spine, some of them would have even had muscle biopsies, skin biopsies, some of them even brain biopsies to try and get to an answer. And all of that is so much better these days with advance in genetics. I mean, it's really change in the diagnostic odyssey for families is really important. And that's really, I guess, where my PhD and subsequent research has kind of focused on.
[00:07:43] Speaker A: Oh, it's quite striking. Thanks, Manju. And then touching on your work. So you're currently based in the ZEID center for Rare Disease in Children. And before we delve into your work a bit more, can you tell us a little bit about the building, who's working in it? And I think it has become a real symbol of hope for rare diseases. So it'd be great to hear more about that, yeah.
[00:08:05] Speaker B: I mean, honestly, I feel so privileged working there. It is one of a kind. It is absolutely one of a kind. I don't know anywhere that has such a huge focus on rare disease in children that really amalgamates the kind of scientific progress and scientific work together with translational elements like our Vector facility where we can produce gene therapies and new treatments to then being able to be also in the same building as where we see patients. So it's really special. What's really nice about the ZCR is that there's a common entrance and it's where patients and their families will enter to come and see clinicians in clinic. But it's also where scientists enter to come and do their work, which is focused on finding answers and new treatments for children with these rare conditions. And that's really special. Everyone using the same entrance to kind of achieve the same goals really.
The building is so new, it's so purpose built. We have the most amazing main laboratory that you can see from the street entrance. I always see people taking lots of photographs because it's just so beautiful and it's very lovely to work there, you know, the big open space, the airy space, it's really good for kind of scientific thinking. We have the most amazing, what we call tissue culture space which are specialist HUDs where we grow cells and we have a facility that we can produce gene therapy drugs, which is really quite amazing.
And the whole place is very open plan. So if you go to the different floors, you'll see one of the many 40 PIs working, collaborating, sitting, discussing projects that are cross disciplinary, kind of, you know, across their different specialties.
And having that kind of cross fertilization of ideas is really what drives the science, you know. And at the same time when you're having those conversations, you can see a little window where there's children with their families waiting for their appointments, waiting to be seen with a hope of new treatments, you know. So I think both the science drives the kind of, kind of the patient new treatments, but also seeing the patients drives the science. It's the perfect example of how science should be driven for translational research.
[00:10:28] Speaker A: Oh, thank you, Manju. You describe it so beautifully. And I don't think there are many places in the country where you can do translational research in the way that you can do in the ZEID center. And as you say, with it all being under one roof. So maybe going back to your research and your world is about neurology and genetics and they come together so you Mentioned, mentioned that you work in rare neurogenetic movement disorders. Can you say a bit more about those? Yeah.
[00:10:58] Speaker B: So I mean, that's really an umbrella term that we use to describe children and young people that have problems perhaps with their development or their motor function. So their ability to talk and walk and to learn things. And it's a big umbrella. But really what we focus on is those that have genetic forms. So diseases caused by a single gene. And these are rare, and we've been working on them for the last 10, 15 years now, trying to find answers for families, trying to understand the disease mechanisms and then allowing that to then lead on to new treatments. And I mean, I've got a few examples. Probably one of our best examples is our work on a condition called KMT2B Dystonia.
This was a genetic discovery we had in the lab a few years ago where we would see patients in our clinic that had walking difficulties. And many of them were thought to have a form of cerebral palsy from brain injury. But what told us that it wasn't brain injury was the fact that they were progressing over time. And some of them even had siblings, so brothers or sisters that were similarly affected or a parent that was similarly affected. So that gave us a strong idea that this was something genetic. And we found a new gene that was the cause of their medical problem. And we were then able to find a treatment called deep brain stimulation that actually works for these children. And that treatment involves stimulating a part of the brain that it helps control the movement problems and allows these children, many of them, to walk again from not being able to walk before and improvements in their speech. So a real transformative treatment.
And what was nice about that was that now this gene is actually probably one of the commonest genes that causes genetic forms of movement problems in children.
And it's worldwide. There's thousands of patients described now with this condition.
And that there was an existing treatment that we were able to apply to these children. So that's great. But we also work on single gene disorders where perhaps there isn't an obvious treatment. We have some very good examples of that. There are some childhood forms of Parkinson's disease. So just like the adults, these children will have walking difficulties. They're slow to walk, they can't speak, they have less facial expression, they have tremor or tremulous movements very much like adult Parkinson's disease. And these children, there is no treatment and often it's a very life limiting condition. And through the work for the last 10 years, a lot of which has been done in the zcr.
We've developed a cell model of this condition. And what we've done is taken skin cells from our patients when they've had skin biopsies for testing in the hospital. And we've grown those cells and we have these state of the art kind of technologies that convert those skin cells into brain cells. And we've been able to use those brain cells, in addition the laboratory, to trial new treatments such as gene therapy. And now they're really accelerating towards kind of trial. So we hope to be in trials for these conditions with these gene therapies very soon.
[00:14:30] Speaker A: Oh, it's amazing. And what we were able to now achieve, and it must be incredible, incredibly rewarding seeing the change for patients. And you talked about deep brain stimulation. I know that's becoming increasingly important, but more generally, it would be really good to hear about some of the challenges in treating pediatric neurodevelopmental disorders.
[00:14:53] Speaker B: Yeah, I mean, it's such a good question. I think I would say that the main challenges relate to disease rarity. I think that's what I find really tough.
So by absolute definition, when you're dealing with a rare disease, finding people with a real specialty in that disease or understanding is very difficult because the patients we look after are globally dispersed, they're all around the, around the world. And, you know, even a specialist clinician may have only seen three or four patients. So to try and understand what happens in the disease naturally over time is really difficult. You know, trying to kind of get large numbers of patients to really, really understand the disease and the spectrum of disease is really difficult.
I think the other things we kind of face when we're looking at this group of pediatric developmental disorders is that unfortunately, in addition to not understanding the natural history of the disease, often these diseases don't have easy biomarkers. And what I mean by that is a way for us to kind of measure how severe the disease is and how it's changing over time. That we don't have an easy blood test or a urine test or another form of testing, maybe a scan or something that can tell us how the disease is changing. And ideally how the disease is changing before it happens in the children is what we really need to know.
So that's a major kind of challenge, I would say also the other major challenges is sometimes we want to know about these conditions when children are born so that any treatments we develop have maximum impact. And without good newborn screening programs where children are screened from very early on at the time of birth, it's impossible to have that what we call the therapeutic window or that window of opportunity where we can give a treatment for maximum benefit.
And then another major challenge for us is that working in rare disease, it is that added challenge of trying to entice pharmaceutical interest for us to develop these drugs. So when we work on a condition and we find a new therapy, it is very hard then to engage. Even if the therapy is really effective in our models, it's really hard to engage industry because, you know, the financial return for rare diseases. So I think overcoming all these challenges is really important. I think overcoming many of them will allow us to progress to more disease modifying treatments for these pediatric neurodevelopmental disorders.
[00:17:29] Speaker A: It's really challenging, isn't it? For the reasons that you say and also the impact on the child and their family. It's quite profound, isn't it? Day to day living with an illness.
[00:17:38] Speaker B: Exactly. And it's just that really accentuated in children, even, even more so than adults. I think in some ways, you know, that, you know, you know, I definitely find in clinics some of the hardest diseases I have to break diagnoses to families are all related to those ones that are progressive and degenerative. To be told that your 2 year old or 3 year old has something degenerative must be absolutely devastating. I can't think of, you know, and their desires for new treatments and new trials is overwhelmingly important and really should constitute research priority, in my opinion.
[00:18:13] Speaker A: I think that's really true. And often you find those families want to do something for future generations, don't they? And it's just their contribution to research is just so important. So important.
[00:18:24] Speaker B: Yeah.
[00:18:25] Speaker A: So Manji, you've mentioned gene therapy, which is one of our USPs here at Great Ormond street and the Institute of Child Health. Can you say a little bit about what it is in simple terms?
[00:18:38] Speaker B: Absolutely, yes. So gene therapy is just a medical term that we use where we try and treat the symptoms of a disease by trying to really address the problem. Okay. And that's actually your gene. So it may be that you have a condition where you have a spelling mistake or a fault in a gene and that faulty gene causes the disease. And what we are aiming to do with different forms of gene therapy is to swap out the faulty gene for a healthy gene.
Another approach may be that you try and give a brand new gene. All of this to try and help fight the illness or replace the kind of effects of the faulty gene by giving something healthy back. And it's, you know, gene therapy has been used for all sorts of conditions, lots of different genetic disorders, certain types of cancers and even for viral infections. I mean, even the treatment of COVID has been through kind of genetic vaccines as such. You know, many of them are still in clinical trial and there's a long way to go. But there are some licensed treatments emerging and certainly within our field we are starting to use genetic therapies even in the NHS and in the clinic now.
[00:19:54] Speaker A: Yes, and it would be great to hear a bit more about that. So focusing in on your specific work, how have gene and cell therapies evolved when it comes to treating children with neurodevelopmental disorders?
[00:20:08] Speaker B: So, I mean, I think probably the best example I have, there's several examples, but probably one of the most advanced examples is that of a condition called spinal muscular atrophy, or SMA as it's called. And this is a very severe neuromuscular condition where children are very weak and have a life limiting condition. And there are now licensed therapies within the NHS that can really change the outcome with improved survival and development of motor milestones. Really, really amazing. And that's given as an injection into the body to try and treat the muscles that are affected.
Personally, we've just been. As a personal example, my service at Great Ormond street has just been commissioned by NHS England to deliver the first brain delivered gene therapy for a very rare condition. The condition has a long name, it's called aromatic L amino acid decarboxylase deficiency, or we call it AADC deficiency. But in very simple terms, children with this condition don't have enough of some very important brain chemicals known as dopamine and serotonin. And these chemicals are really important for your development, for controlling your walking and talking. And many of these children have a very life lim used to have a very life limiting condition where they'd be at risk of sudden death or most of these children would not even raise their heads, let alone develop any further milestones such as crawling or sitting or walking. So the most they would achieve is partial head control and not more than that. And now there's a gene therapy that's licensed in the NHS that we're able to deliver. And these children have quite a long operation to allow that gene therapy to be delivered into a very specific part of their brain. And we've seen some very, very good results. So these children are now able to develop much more, they're able to talk and develop much more milestones like sitting and walking in some children previously Many of them would have these very life threatening episodes where their eyes would get stuck and their bodies would be very stiff and many of the children treated now those episodes have disappeared, you know. So I think the AADC gene therapy is a really good example of how you can really modify disease from potentially a child that's not able to walk, talk or even raise their head and has life threatening episodes to someone where those episodes are gone, they have less medication, they're able to feed orally, they can talk, they can sit, some of them can walk.
You know, it's really quite life changing, you know. So the goal of getting these therapies from ideas into the laboratory, to look at disease modifying treatments in our laboratory models to then into the clinical trials and then into the NHS is really the goal.
[00:23:18] Speaker A: It's absolutely incredible. And the fact that we're now treating children with these therapies, that they're being adopted by the NHS and their quality of life must be completely different, as you say, to what it was and that they're surviving a lot longer, aren't they, than they as well. So it's, it's really.
[00:23:36] Speaker B: Families are just so happy. I think it makes such a difference, you know, But I mean, yeah, it was, it was, it felt very exciting to be setting up a service like this, you know, I mean, I always tell the story of how with the first surgery that we did, the first patient who had this surgery, we were in theater and our pharmacist came down with our epic, which is our electronic system that we use at Great Ormond Street. And in the same way as I prescribe, almost the same way as I prescribe paracetamol, I was able to prescribe gene therapy which felt very amazing and pioneering.
[00:24:10] Speaker A: And yeah, it's quite an important moment, isn't it? Good milestone. Yeah, absolutely.
So there's been a huge amount of exciting progress in this field. What do you see as the main barriers to pushing this research forward, especially around the gene and cell therapies?
[00:24:28] Speaker B: Yeah, no, the major one I would say is funding, it's definitely funding. These gene and cell therapies are not cheap, they're expensive.
And I think really even looking across the board, globally, I think where there's lots and lots of money injected into these therapies, they're the ones that develop the quickest.
And even though I think, you know, industry investors, venture capitalists, pharmaceutical companies all recognize the huge impact that these gene therapies can be, can achieve for children on a one to one basis, I think persuading them to take on these rare disease projects is a major challenge, you know, because of financial return. I think we need to seek alternative paths on how we can perhaps work with industry and work with other, possibly philanthropic funds on how this can be achieved for children with rare disease.
We have seen from time to time that very, very exciting gene therapy programs are developed for children with rare disease and hope is extremely high from families. And for commercial viability reasons, often these programs are dropped. And we need to think about ways in which these programs can be rescued. I think that's a really important thing that within the rare disease field we need to think about and then regulatory landscape needs addressing that.
Developing each gene therapy is time consuming, requires interaction with our regulatory bodies for each kind of disease and each indication, and maybe there's ways in which that process could be more streamlined and effective to further accelerate the development of these therapies.
And I think moving forward as well as more and more of these treatments are coming to the clinic, I think it's important that we think about bioregistries. And what I mean by that is having the ability to be able to record what happens to our patients, where we are administrating these gene therapies. And I don't just mean within the trial, within the two or three years of a clinical trial, but looking at them long term for 10 to 20 years to be able to really understand what impact the gene or cell therapy has had and how the children have developed, what side effects they've had, what long term effects they've had.
Both good and any kind of that haven't been good. So then we're able to take that back to the laboratory and develop even better second generation therapies.
[00:27:18] Speaker A: Oh, it's such a good point. And it's an area that we need to have more emphasis around, don't we? Especially as you say, the adoption into the clinic and how we work with industry and making sure that everyone, they're ready to take these on because they don't always have a commercial return because they are so rare, aren't they?
[00:27:40] Speaker B: Yeah. And I guess adding to that as well, I think as more and more gene and cell therapies are approved into the clinic, which means that potentially a number of different NHS and global centers are able to administer them, is how do we ensure that each treatment is delivered well, you know, that it's delivered well and to high clinical standards in each centre. I think that's again a challenge as the increasing availability will naturally make us want to make sure that Everywhere that delivers these complex therapies is well trained and well equipped to deliver them. Well.
[00:28:19] Speaker A: Yeah, you're absolutely right. And I think there's a lot of work in this space, a lot of innovation, working with regulators and others. So we're coming to the end. Manju and I thought we could finish up on talking a bit more about the ZEID center and the work and why it's so crucial and especially around the advancement of gene and cell therapies. And you touched on this a little bit earlier, but I wonder if you had any concluding remarks around the facility and its importance in this space.
[00:28:48] Speaker B: I mean, I think it's crucial, I think, I think over time a form of core funding, quite possibly for the center.
I mean, I'm being very ambitious about thinking this, but there are centers around the country, for example the MRC centers, core MRC centers that are core funded. The idea of bringing core funding to a center like the ZEID Center I think would really advance science.
I think it would take away the need and I think core funding would allow us to develop important facilities that are needed within the ZCR that we can develop and enhance with that core funding. I think establishing strong collaborations both nationally and internationally with key other centers that work on translational research will really help us push the boundaries.
As I said, developing and honing our core facilities that are signature. So the combination of our vector facility where we produce the gene and cell therapies, our kind of genomics facility, our laboratory facilities, making them all very core, I think would be very, very important. And then I think more training for the staff that work there in transcending from the basic science to the clinical trials and then bringing them to the clinic, that kind of approval process that, you know, as we get better at that, our chances of having more licensed treatments increases, which will be very, very exciting.
I think the ZCR is, well, kind of designed for a multidisciplinary collaboration, but I think expanding it even more than we're doing at the minute. So within the center we have good interaction between immunology, neurology, pediatrics, genomics, respiratory, so lung work, many, many things. But you know, bringing in things like that we wouldn't naturally think of like bioengineers to help us design the best systems and kind of for us to do some of our research, mathematicians, engineers who are very good at producing next generation gene therapy vectors, all these sort of things, thinking beyond or what capabilities we have to kind of unusual collaborations that would really bring on our research I think would be also Very important.
[00:31:24] Speaker A: So thank you. Manju, as you say, the core facilities are such a crucial part of the building. They're part of the buildings USP and they allow us to accelerate new treatments for rare diseases and they're critical to our success as a research hospital and also the work that the institute does in the wider university.
So I think we've come to the end now and it's all the time that we have for today and it's been such a wonderful conversation with you, Manju. Thank you. We've covered so much from the promise of gene and cell therapies for pediatric neurogenetic disorders to the incredible work that's happening in the Zyde Center. It's really amazing to hear about all of the progress that has been made, especially in your field, but also the challenges that we still face in pushing these groundbreaking therapies forward. I always love speaking to you and you're changing patient care and patients lives on a day to day. So thank you so much for all that you do.
[00:32:28] Speaker B: Thank you very much, Kiki, for having me. I completely agree. I think whilst there are the hurdles we've talked about, really I agree that at the zcr, the Zeitz center for Research, we have real potential to change the lives of children with very complex conditions, you know, for their families and improve longevity of life and quality of life, you know, is really what we should be doing.
[00:32:49] Speaker A: So thanks so much Manju for joining us and for sharing your insights. It's really clear that gene and cell therapies are opening new doors and centers like the ZEID center are leading the way in not only research, but patient care and advocacy as we spoke about to all our listeners out there. Thanks for tuning in. If you're as fascinated by today's discussion as we are, make sure to keep an eye on how this field is evolving. It's definitely one to watch. Thank you.
