Expanding the Gene Therapy Toolbox: Dr. Bobby Gaspar, Co-Founder & CEO of Orchard Therapeutics

Lindsey Smith 

Hi, I'm Lindsey Smith, welcoming you to Raise the Line with Osmosis from Elsevier an ongoing exploration about how to improve health and healthcare. 

Today's episode is part of our Year of the Zebra series, which shines a light on rare disorders and the people impacted by them. If you're not familiar, the Year of the Zebra is a bold and inspiring initiative launched by Elsevier Health a few years ago, and we've proudly continued the work ever since. The goal? To raise awareness among health professionals, caregivers, researchers, patients, and the public about rare diseases, often referred to as zebras in the medical world. 

This spotlight on rare conditions couldn't be timelier. While the pace of innovation is accelerating, only about 50 gene therapies have been approved so far by the US Food and Drug Administration. Our guest today, Dr. Bobby Gaspar, is at the forefront of this frontier. He leads Orchard Therapeutics, a UK based biotech company responsible for developing one of those rare, approved treatments. The therapy in focus is lenmeldy, the first approved treatment for metachromatic leukodystrophy, also known as MLD, a devastating inherited disorder that affects roughly 600 children worldwide. 

Today we'll explore how this breakthrough therapy works and its use of the stem cells that form blood and immune cells. Dr. Gaspar also serves as an honorary professor of pediatrics and immunology at university college of London and was recently named one of the Time Magazine’s 100 Most Influential People in Healthcare for 2024.

We're honored to have him with us. Dr. Gaspar, thank you so much for joining us.

Dr. Bobby Gaspar 

It's a pleasure. It's real pleasure. Thank you for inviting me. It's great to talk to you.

Lindsey 

So I'd like to just start by learning more about you and what first got you interested in medicine.

Dr. Gaspar 

That's an interesting one. a good one to start off with. Well, medicine was always in my family, so that was the first thing. My parents were both doctors. Coming from an Asian- Indian background, medicine is kind of highly sought after, and with both my parents being doctors, and they enjoyed their work, you they talk about at home, all their friends were doctors, I almost felt that there was no other profession to go into. I'm the oldest of five children. I remember my mother once sitting us all down and she said, “I don't care what you do, as long as one of you is a doctor.” And four out of the five became doctors! 

Lindsey 

Wow, that's incredible.

Dr. Gaspar 

So, there was always that background. But I think more importantly, as I went through school, I was kind of toying between medicine and maybe doing classics. I ended up kind of gravitating towards doing science. Really, you're interested in all kinds of things, but I remember studying the discovery of DNA, the Watson-Crick story and everything, and even at that stage -- so I must've been 17 or so -- I just thought that is so fascinating. The fact that these chemicals, this DNA, somehow influences everything that we do...that was kind of mind blowing to me. 

So that was the first kernel that I had that not only did I want to be a doctor, but I wanted to be involved in something that was right at the root of what we are all about as humans.

Lindsey 

That's a really great story and just want to come back to the four out of the five siblings being doctors. Incredible, absolutely incredible! 

Dr. Gaspar 

By the way, the fifth is a psychotherapist, so she's in the profession as well!

Lindsey

Okay, so you guys are doing pretty good over there! I think it's always interesting to hear what sparks someone's path into medicine, so thank you so much for sharing that. 

So, ultimately you end up in gene therapy. Gene therapy has been approved as a treatment for several rare inherited diseases, and there's ongoing research to find ways to treat it even more today. When did you first get involved in gene therapy and what brought you into that?

Dr. Gaspar 

Yeah, so as said, that fascination with DNA was there for me when I went into medical school. I was the kind of medical student that when you're on rounds and everything else and the seniors are talking about diseases, I was always the annoying one that asked why that disease? Why that, not necessarily how you treat it, but why? I wanted to understand the basis behind these diseases. So, I think I was always quite curious. 

During medical school, we could do a year of science and I took out a year to do science with some lab work that was focused on genetics -- very, very early kind of experiments on cloning and things like this -- and it kind of just got me kind of interested in that whole area of genetics and potentially genetic manipulation as well. So when I qualified as a doctor and I started my early stages and I went into pediatrics, I knew even then that at some point I'd want to do more research just because I was curious about what kind of research or which field of research. I had no idea. I just knew that sometime at some point I wanted to explore that more. 

And so what happened was I was training as a junior doctor in pediatrics and I went to Great Ormond Street Hospital, which is a specialist hospital -- a bit like your Boston Children's or CHOP in the States – and it was at a six month job in the area of pediatric immunology. So I was looking after kids with very rare diseases, kids with single gene disorders who had problems with their immune system and they couldn't grow an immune system. These are the kind of the bubble babies that you hear about. They're prone to all kinds of infection.

These kids were really sick. I mean, really ravaged with infection, and most of them would die or the only treatment at the time was a bone marrow transplant and many of them would die from the consequences of a bone marrow transplant. You saw the difficulties that they went through and their families went through. 

I was the most junior member of the team and I remember looking after one child who had this severe immune deficiency. I asked the question to the professors, how are we going to treat this child? This was back in 1992. And they said, this child's going to have gene therapy and they walked on. I genuinely thought it was a joke that they played on the most junior member of the team, because I'd never heard of it before. And I thought, you know, what are they talking about, but this was the first individual of any age that was going to be prepared for gene therapy in the UK. I just thought this was amazing. I thought this was science fiction medicine. I was fascinated by it. 

At the end of that six months, they wanted to be a fellow to be involved in the care of the child, because there was so many logistics that nobody had gone through before. I just put my hand up and said, look, I'll do it. I didn't know where this was going to lead. I just thought it was fascinating. So, I was involved in the first gene therapy treatment in the UK. It involved preparing the ethics application, preparing the protocol, preparing the child in many ways. In the end, we were actually infusing the gene modified cells into the child, and it didn't work for that child back in 1993, but I just thought there's a future of medicine here that is just extraordinary. 

And even though it was for a very, very rare disease, just the fact that it was so interesting technically and scientifically, and also potentially had the ability to kind of change a disease at its fundamental core, using genetic information to change the course of a disease was just totally fascinating to me. So I just thought I want to be part of this and that's how I got into it.

Lindsey 

That's amazing. You've been right in the middle of it from the very beginning. I want to talk a little bit about the type of gene therapy pioneered by Orchard. How does it work and what differentiates it from other approaches?

Dr. Gaspar 

That's a great question and I think it's a very important question, actually, because when we say gene therapy, we kind of use that term loosely. But in fact, gene therapy is many different types of technology, all involving the replacement of genes. They're all very, very different and it's important to distinguish between them. 

So, the type of gene therapy we do is called -- and this is what I talked about with this girl with the immune deficiencies -- hematopoietic stem cell gene therapy. Essentially we are modifying those blood stem cells. So there's a gene that is defective in blood stem cells and we're taking out those blood stem cells. We used to do it actually directly from the bone marrow through an operation, but now we can do what's called a leukophoresis. So we mobilize the cells into the bloodstream, we take out the cells out of the body, we actually isolate that blood stem cell population and in the clean laboratories, we introduce a working copy of the gene that is missing into those cells. 

So those genes, those stem cells, are now gene modified. They contain a working copy of the gene. And then we reintroduce those cells back into the bloodstream, they find that we're back to the bone marrow. Let me just talk about the immune deficiencies first of all. Where we started is that the white cells, the immune cells, can't grow because there's a problem in the bone marrow cells. And so now you're introducing the working copy of the gene into the bone marrow cells. That means that the white cells can now grow, they can function normally and they can fight infection. 

Now, it's been used for red blood cell disorders as well because those blood stem cells can give rise to red blood cells. So if there's a problem in red blood cells, such as in sickle cell disease or beta thalassemia, by putting the gene back into the stem cells, you can now allow red blood cells to grow and function properly. It's about correcting those hematopoietic stem cells and allowing them to give rise to cells that can then correct the disease. 

One of the things about it that is, I think, differentiated maybe from other forms of gene therapy is the kind of longevity of the approach because one of the things is that we've used lentiviral vectors to introduce the gene into the stem cells. What lentiviral vectors do is they splice the new genetic material into the genome of the target cells, which means that with every cell division that new genetic material is passed on. So, even when they differentiate from being blood stem cells into white cells or red cells, that new genetic information is passed on. 

Secondly, hematopoietic stem cells have the potential to self-renew. So when you engraft these new gene-modified cells into the body, they self-renew. Their gene-modified cells are potentially there for the lifetime of these individuals. So a single administration can give you potentially a lifelong effect.

The first child that I treated successfully was in 2001 and that boy has finished college, he's living a normal life, he posts on social media, et cetera. So you can see that a single administration has been able to correct his disease for over 20 years now. So it's very, very powerful in that you're essentially, through this mechanism, able to hopefully provide a cure for somebody through that approach.

So just the final point is, there are different types of gene therapy and hematopoietic stem cell gene therapy can correct certain genetic diseases. It can't do everything. It can't correct a disease of the liver, for example, we don't think, but other gene therapies are able to get to other different systems. So I use this analogy of a toolbox and think of each gene therapy as a different tool. And for certain indications, for certain diseases, you'll need that particular tool, but that tool won't be able to do everything. So, use the right gene therapy for the right disease.

Lindsey 

It's fascinating how gene therapy works and how you're going in and fixing that faulty gene and also the fact of the longevity of it -- just giving that one treatment can potentially lead to a cure -- is incredible. 

Dr. Gaspar 

That's amazing. Yeah.

Lindsey 

We've heard from other guests in the rare disease space talk about the difficulty in conducting clinical trials because of the small pool of patients to draw from. How did you overcome that challenge?

Dr. Gaspar 

That’s a very important question. I think part of this is having very good networks with physicians and patient populations as well, the patient support groups, because in some of these diseases, the ones that we've dealt with, these are devastating conditions and there's very few therapies or no therapies available.

The community is very closely tied together to look for the best outcome for these conditions. So the patient support groups and the key opinion leaders work closely together. And so certainly when we did trials in the academic setting or even when I formed Orchard and we've conducted trials, we're very, very closely connected with the stakeholder community. You make your trials available to the community and that word spread and therefore you can draw upon essentially a global population of patients. 

In the trials that we've conducted, they're not just coming from one country, they're coming from multiple different countries around Europe or from the U S and coming internationally as well. So you're recruiting on a global basis and that does allow you to be able to find patients to do these trials. And obviously, those first trials are relatively limited trials. There are tens of patients, there are not hundreds of patients. So you can do that in a fairly effective timeframe by having that connectivity and that relationship with the stakeholders of physicians and patient support groups, and they've been absolutely instrumental in making this happen.

Lindsey 

Yeah, I think that community piece is so critical. We've talked to many parents of rare disease patients and just talk about how they form this village around them made up of other parents, researchers, doctors, kind of sharing that knowledge and what's happening.

Dr. Gaspar 

You know, it's so powerful. It's so powerful. You bring everyone together as we've done. You're absolutely right. You form a kind of village, a community of multiple different stakeholders all trying to work towards finding the best outcome for these terrible diseases.

Lindsey 

Exactly. Let's talk about newborn screening. We know it can play a crucial role in early detection, especially for rare genetic conditions. Can you talk about how it intersects with the impacts and impacts your research and development of gene therapies?

Dr. Gaspar 

Yeah, so I've been a very, very passionate advocate of newborn screening for these conditions because I see how devastating they can be and, you know, in some cases, if you diagnose these patients too late, then it's very, very difficult to offer a good outcome. So the earlier you can diagnose, the better the outcomes are. 

What we've seen is actually when you've got an individual in the family who has got one of these diseases -- and sometimes it's too late for that individual -- but you screen the younger family members. And because they're genetic conditions, you can find other siblings who have got the same mutations, but they haven't yet developed the disease and then your interventions are so much better for those unaffected younger siblings.

Sadly, we're having to lose older individuals in order to be able to save the younger individuals because we can diagnose them early. So, if you can diagnose everyone early, then you've got a better chance of offering a better therapy for those individuals. And you can really only do that through systematic newborn screening of all babies. 

For certain diseases, where it's absolutely crucial to intervene early before symptoms have started, you've got to have newborn screening. We are in a position where very effective therapies exist, but we can't unfortunately give it to all patients because they're diagnosed too late, and the only way we can offer these effective therapies is to find them at the earliest stage possible through newborn screening. 

Both in my academic life and also through Orchard, we have been very focused on advocating for a newborn screening for these conditions, and that's only the ones that we've dealt with. There are many other conditions that other support groups have also advocated for as well. It's true preventative medicine. It's true preventative medicine. There are conditions now where if you can diagnose them early and you can offer these kinds of potentially curative therapies, families and individuals will never see the disease. They just won't see the disease at all, and so you will change the landscape of a disease by being able to offer universal newborn screening and these potentially curative genetic therapies.

Lindsey 

Yeah, that's incredible. We just had a NICU nurse on earlier this week who also reiterated the importance of these newborn screenings and catching these conditions early because it really can change everything for those families. 

I want to talk about what other diseases that you and Orchard are targeting beyond MLD.

Dr. Gaspar 

Yes. So, we started off with these conditions like MLD which are very severe neurodegenerative conditions. They're part of a group of conditions called lysosomal storage disorders, where there is a single gene defect that leads to an absence of a lysosomal enzyme, and that leads to the buildup of certain substrates in different parts of the body. In MLD, there's a particular buildup in the neurons. The question is, by seeing some of the effects that we've seen on MLD, can we use the same approach for other lysosomal storage diseases? 

So, we now have a program in MPS 1, which is Hurler syndrome. It's a different lysosomal enzyme that is missing, but it also causes substrate buildup, not only in the brain, but in the skeletal system, the heart and elsewhere as well. There's been a proof of concept study that shows some very effective outcomes in neurodegeneration and on skeletal function as well. So that's going through a pivotal study at the moment. So that's very, very exciting. 

We have proof of concept data in another lysosomal storage disease called MPS 3A, and that's in the clinic as well. So there's clearly the potential to have a real impact on these lysosomal storage disorders beyond the three that I've talked about. 

That in itself is extremely exciting, but you can take some of those learnings from these rare disorders and apply them to much larger conditions as well. So that now takes us from rare to, you know, much more common and being able to treat not just tens or hundreds of individuals, but potentially thousands of individuals. And we’re doing that through other programs that we are working on. 

There's a condition called frontotemporal dementia, which is actually another form of neurodegeneration that affects older individuals. With the learnings that we had from MLD, we've been able to apply to develop a program for this much larger form of dementia. So the learnings from the rare were taken to the more common.

We've also got a program now that's going to go into the clinic in the next couple of years for a form of Crohn's disease as well. So that's for a specific genetic form of Crohn's disease. And again, this comes from our learnings in the rare disease space. What we've found is that these gene-modified blood stem cells can give rise to macrophages that are able to migrate into tissues. So they migrate into the kidney, they migrate into the liver, but they also migrate into the gut as well. And so by understanding the mechanism of this one specific form of Crohn's disease -- which seems to be a disorder of macrophages -- we can actually replace those defective macrophages with gene modified macrophages and hopefully correct this form of Crohn's disease. We've done preclinical studies in murine models which show that this may be effective and hopefully can translate that into

into the clinical setting. That would be very exciting. 

So you're taking those learnings and applying to something that affects, let's say, thousands of individuals.

Lindsey 

Yeah, I liked what you said there...taking the learnings from the rare and applying them to the more common problems that we experience today. Really exciting stuff on the horizon for you guys. 

I want to talk about the cost of gene therapy. They do come with a high cost, in part because they're so personalized. What efforts are underway to make these kind of treatments more accessible and affordable for patients who need them most?

Dr. Gaspar 

Yeah, they have had that tag of being very expensive, but it’s good to just set that in context because I think what you have to think about is the value that these medicines actually provide. And when you think about value, you look at what currently exists for those conditions and what you are offering and what's the difference between what's available now and what you're potentially offering. 

So if you take a condition like MLD, there was no approved therapy. It was essentially supportive care and there was a huge burden both on, obviously on the child, but on the families, on the healthcare system around. Suddenly, you come in with a therapy that is given once and potentially has a lifetime effect, and if you intervene early, those children may have potentially normal lives as a result of that intervention. 

What value do you ascribe to that? And so when MLD was assessed by, for example, NICE in the UK -- where they assess the value of medicine by quality adjusted life years which is by how many years does this medicine prolong life and what is the quality of life that it affords over that time -- they gave it more qualities than any other medicine that they've approved. So, that’s one important thing.

The other context is we currently have medicines that are reimbursed, which have to be given every week or every month and they have to be given for the lifetime of an individual. And that might cost hundreds of thousands of dollars per patient per year, so over a 10 year, 20 year period, it runs into millions and millions of dollars. What we're doing is offering something once. And so I think there's this kind of gap between what we're prepared to pay for now, but because we pay it regularly, that's different to what we're prepared to pay for now when you have to give it all at once. So I think we have to just kind of think about the different contexts there. 

In terms of what will happen in the future, I think there will be ongoing discussions between reimbursement agencies and companies that are making medicines. You know, these medicines are for a handful of patients in every country. So, their impact upon a larger budget is pretty minimal, which is one thing. So, I think the term in terms of access, that we've not certainly not seen any difficulties for patients to access these medicines because of cost. Because the value is so great, the reimbursement agencies are prepared to be able to offer that treatment to patients.

Lindsey 

That's really helpful context. And you're right. It's such a different model than I think we're all used to with that one time treatment, for a lifetime potentially. So you've been recognized as a pioneer in gene therapy development . With that perspective, how would you describe the current state of the field and where do you see it heading in the next few years?

Dr. Gaspar 

Thank you very much, that's very kind of you. I've been in this field a long time and I've seen it kind of evolve in many, many, many phases and I think it's been a bit of a roller coaster ride. It's always been, touted as the future of medicine. Then there'll be setbacks and everyone goes, my God, this just doesn't work and everything else. And then it kind of has another phase, et cetera. So I think we have to take all of that in context. 

There will be gene therapies that will be the standard of care for certain diseases, but it won't be for every disease. As I said, it's that kind of toolbox approach where for certain conditions, some gene therapies will have a real effect and they will end up being the standard of care. And it's just choosing where that gene therapy. What is the indication? What is the underlying disease defect? What is that mechanism and can gene therapy provide the optimal solution for that? So I think that is absolutely key. 

One of the other aspects has been the manufacturing issues as well, which are getting better and better over time, but have been more difficult, more complex, more expensive. But again, innovation provides solutions to that and will lead us to more streamlined manufacturing solutions, which lots of companies are working on, and certainly we are as well, so that will also make it much more accessible and affordable in the future. 

In the current state, we must not take any kind of knee jerk reaction. I think we have to take an objective view on what gene therapies can move forward for these indications. I think if that is the case, then we will have very many gene therapies available and they will meet the standard of care and offer real, transformative outcomes for some very, very severe diseases.

Lindsey 

It's really exciting to imagine the impact that gene therapy is having and is going to continue to have as we continue to make more progress with innovation along the way. 

So, at Osmosis, we are a teaching company and we're always looking to close knowledge gaps. Today, in our Osmosis platform, we do have a video on MLD, but I wanted to know if there was a particular topic, maybe something that might be overlooked or relevant in the work that you do that you think Osmosis should cover.

Dr. Gaspar 

Yes. Especially when you're talking about MLD and some of these neurodegenerative conditions, I think what would be interesting is just to demonstrate how blood stem cells correct a neurological disease, because that’s one question people have. You're giving these gene modified cells into the bloodstream, yet somehow they're protecting the

the brain. The reason for that is these blood stem cells -- especially cells of the macrophage myeloid lineage -- have a license to cross the blood brain barrier. So the blood right there is usually designed to keep things out. You know, that's why it's so difficult for certain medicines to get into the brain. But these are natural cells and they have a license to get into the bloodstream. 

So by putting your gene into the blood stem cells, they naturally through that process get into the CNS, get into the brain, and there they become microglial cells that can express this new gene product that can be taken up by neurons and therefore protect neurons from neurodegenerating. So I think these kind of mechanisms are really important to highlight from a learning perspective. 

I think the other thing that potentially is really interesting -- and the technology around this is advancing so quickly -- is how you manipulate genes. The technologies that are available now to manipulate genes have just advanced so much. We started off with what now would be considered a very old fashioned approach of just inserting a new gene, but now you can actually edit genes. You can actually knock out genes. You can now replace a single base. So you can see if there's a point mutation, you can revert that single base point mutation back to wild type using these base editors that have been developed. And those are going into the clinic now. I mean, it's extraordinary. You could rewrite parts of genes. 

I think for your listeners, for your students, as I said before, some of these will be the future of medicine, so learn about it now because it's going to be there when you're actually practicing as a doctor and you can explain to your patients exactly how this works. 

But that technology to be able to manipulate genes in such a precise manner is fascinating and amazing.

Lindsey 

That's a really great idea. Thank you so much for sharing that with us. Another question for our audience, especially given your background in academia, is what advice would you offer to students and early career health professionals in our audience as they navigate today's complex healthcare landscape and chart their own path forward?

Dr. Gaspar 

The answer I'm going to give you is a very personal one. I don't know if it's the right one, but it is a very personal one. I always think that you just have to be driven by curiosity. I think you have to be driven by what you find fascinating. I mean, medicine is so broad. There are so many different aspects of medicine you'll come across in either a disease or an area of technology, et cetera. But if you think that's interesting and it grabs you, then follow that as much as you can, which is what I ended up doing. 

When I started, people would ask me, why are you doing this? I was working on these conditions where there were a few patients per year identified in the UK, with a technology that was in its embryonic form. And it was purely because I was fascinated by the science, fascinated by the kind of clinical impact that it could have. I would never have anticipated where the field went or where it led me, to be honest. But I think if you're driven by that kind of curiosity and that interest, then number one, you'll always enjoy it wherever it goes, because that's what got you into it in the first place. But I think there's always a way through these things and you'll find a way if you have that desire, that interest and fascination for that subject.

Lindsey 

That's such valuable advice. Be driven by curiosity. Thank you so much for sharing that with our listeners today. Before we wrap up, I've got one final question for you and wanted to ask you what's next for you.

Dr. Gaspar 

Yeah, I just love doing what I'm doing. I've always felt I'm at the start of something, not at the end of something. I always feel there's another disease, there's another condition that needs to be addressed, that needs to be cured. That's what drives me. 

I think of what we're doing and what we've done so far, but there are programs which are in the clinic that are showing these beneficial effects. We have to get them approved. We have to make them available to patients in the lab. We're showing correction of these conditions like Crohn's or a front stem dementia. Now we've got to get them into the clinic. Now we've got to get them down that pathway. So there's always more to do. 

While I still feel fascinated and interested by that, then that's what I want to keep, doing and hopefully have an impact on many, many, many more lives. To be able to make that kind of change is extraordinary. And also, to fashion the landscape of medicine through newborn screening, being able to identify patients earlier and offer these kinds of interventions...that's what drives me and I hope I can continue to do that.

Lindsey 

There is always more to do for sure. Thank you so much, Dr. Gaspar, for joining us today. It's been a true pleasure speaking with you, and we are very inspired by your work and excited to see your continued leadership in gene therapies and how it will continue to shape the future of global health. Thank you so much.

Dr. Gaspar 

Thank you, Lindsey. It's been a pleasure talking to you. Really appreciate it. Thank you.

Lindsey 

That wraps up today's episode of Raise the Line. A heartfelt thank you to Dr. Bobby Gaspar for joining us and sharing his groundbreaking work in gene therapy and rare disease treatment. His leadership at Orchard Therapeutics and his role in developing lenmeldy are truly reshaping the future of medicine for some of the world's most vulnerable patients. 

Through the lens of Year of the Zebra, we're seeing how breakthroughs like lenmeldy offer real hope, not just for patients and families, but for the future of personalized medicine. We're truly grateful to Dr. Gaspar for his thoughtful insights and for blazing a trail in the world of rare disease innovation. 

I'm Lindsey Smith. Thanks for checking out today's show. Remember to do your part to raise the line and strengthen the healthcare system. We're all in this together.