Instant Genius - The gene therapy future has arrived

Episode Date: June 27, 2024

Right now, in hospitals around the world, patients are being cured of diseases once thought untreatable. The reason? A gene therapy revolution means that what was once the stuff of science fiction is now becoming a reality. One person who’s been at the centre of this medical revolution is Dr Bobby Gaspar, a professor of paediatrics and immunology at Great Ormond Street Hospital and University College London, and CEO of Orchard Therapeutics. Bobby guides us through the complex world of gene therapy, explaining what it is, what it can do and where it’s going. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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Hello and welcome to Instant Genius, the bite-sized masterclass in podcast form. Each week, you'll hear from world-leading scientists and experts, talking about the most fascinating ideas in science and technology today. I'm Tom Howard, trends editor at BBC Science Focus. Right now, in hospitals all around the world, patients are being cured of diseases once thought to be untreatable. The reason, a gene therapy revolution means that what was once the stuff of science fiction is now a reality. One person who's been at the center of this medical revolution is Dr. Bobby Gaspar, a professor of pediatrics and immunology at Great Almond Street

Hospital and University College London, and CEO of Orchard Therapeutics. Today, Bobby guides us through the complex world of gene therapy, explaining what it is, what it can do, and where it's going. Bobby, thank you very much for coming on to Instant Genius today. That's a pleasure. Pleasure, Tom, and thank you very much for giving me the opportunity to talk. What is my favorite subject? Brilliant. So genetic therapies and genetic diseases, you know, it's all very complicated,

bringing it right back to the basics to start off with. Could you maybe explain what we mean by genes and our genetic code and what that does in our bodies? I think this just really comes back to the real fundamentals of what makes us who we are. And this stretches back to Watson and Crick identifying the structure of DNA, of chromosomes. And it was almost talked about as the code for life.

you know, what makes us what we are, and genes are what make us what we are. And there are probably about 25,000 genes that are, you know, essential to making us function, you know, all of the different functions that we all have, all of the characteristics that we have are controlled by our genes. And if I can use a very, very simple analogy, and I, you know, as I said, we talk about it as the code of life, but you can think about these genes as sentences in a book. So, A book has thousands and thousands of senses, but there are some very, very crucial sentences. And that is what a gene is. It's a bunch of chemicals that are making up a sentence. And if there are things in that sentence that go wrong, a word is missing or parts of a sentence are missing or have been deleted, or if there's a crucial spelling mistake, that sentence doesn't make sense.

And then things go wrong. So that's what happens in a gene. You know, there's part of a gene that is missing, there's a mistake in that gene, and that gene doesn't work, and then that can lead to a specific disease. And so what we're trying to do is in gene therapy or genetic medicine, as we're now getting to, is we're trying to repair that essential genetic information. And we can do that now in many different ways. So gene therapy isn't just one thing. It's a number of different ways to correct or replace that sentence, that genetic information. So you mentioned that there's lots of different kinds of gene therapy. What's the common thread between them? How do we go about defining what gene therapy is?

Yes, in the end, I think it comes down to the fact that all of these different types of gene therapy are trying to correct or repair genetic information in order to allow a disease to be either cured or corrected or improved. And I think the way we have to think about it is up until now, we haven't used genes or correcting genes as therapies. We've used chemicals. We've used proteins. We've used enzymes, we've used small molecules, etc. That's not genetic information. That's very, very different. So here we're coming back to the fundamentals of actually repairing, correcting genetic information in order to correct disease. So that's where, you know, we get to the point of gene or genetic therapy. Obviously, I know this can get hugely complicated, but what are some of the main ways

that you can do that, that you can produce these gene therapies to correct that genetic code? Again, the field has evolved enormously so that we have lots of different types of gene therapy. So, for example, the kind of gene therapy that I've been involved in is gene therapy for specific cells in the body. So we are looking at correcting what are called blood stem cells or hematopoetic stem cells. So these are the cells in your bone marrow. If they go wrong or there's a gene in those that go wrong, then it can give right. lots of different types of diseases. And so what you can do is you can take those blood stem cells out of the body and you can introduce into them a working copy of the gene that is faulty. So now you

have these genetically modified blood stem cells and then you can give them back to the patient. And we call it hematopoetic stem cell gene therapy. So that's just one form of gene therapy. and it corrects these blood stem cells. Now, there's another form of gene therapy where, again, you're trying to replace a missing gene, but you want to do it in other parts of the body, not blood stem cells, but maybe liver cells or in muscle cells or in nerve cells.

And there you can put that new gene into a vehicle or a disabled virus, and you can just infuse that into the body. And there the aim is to try and get that. new genetic information, again, into different parts of the body, where, as I say, maybe the liver, etc. And then there are forms of gene therapy, and this gets to some of the newest forms, which is the CRISPR CAS form. And I think a lot of people have heard of that, which is much more precise. And that's very good at knocking out genes. So it might be that there's a gene where the mistake in the gene is harmful. And what you want to do is to knock that gene out.

or you knock out a gene that is part of a pathway in order to improve the outcome. So there you're not replacing a gene, but you're actually knocking out a gene in order, or a harmful gene, in order to get a better outcome. And there are even now much more, you know, very, very specific forms of genetic therapy, where, you know, I talked about it as a sentence with spelling mistakes, and you could actually correct the spelling mistake. You can actually, that very one letter is correct. it can get very specific like that.

So, without making it too complicated, I think of all of these, using another analogy, you can think about all of these gene therapies as different tools. So, you know, you have to use the correct tool for a specific disease. So just like, you know, you've got a hammer. A hammer can do certain things, but it can't do everything. You use it for a specific job. So it's like using that particular tool or that particular gene therapy for a specific disease. You can't use one form of gene therapy for everything. You have to use it for the specific

disease. And now we've got more tools in our toolbox, which means we can address a larger number of diseases. One of the things that you talk about with replacing or knocking out these genes, and I think is useful to drive them to people, is that these changes, unlike our traditional conception of medical treatments, can be permanent. Yeah. Could you kind of just explain how that works in terms of replacing permanently faulty genes? Yeah. So I think this is one of the big things about these new gene therapies is they have the potential through a one-time administration to have potentially a lifelong effect.

So they could be potentially curative. And so that's a big, big difference from what we've been doing up until now. I mean, we normally give medicines, you know, on a daily basis or sometimes a week's basis or even a monthly basis. But now we have the ability to give them just once and then see an effect, as a say, that could last a lifetime. And the reason for that is that, let's say, for example, the kind of gene therapy that we do, where we take blood stem cells, we correct these blood stem cells, we insert a new copy of the gene into these blood stem cells. And what happens is that new genetic information gets spliced into the chromosomes. So we have the

long strings of where all the genes are. And we introduce the new genetic information into those chromosomes. And when that cell, which has got the new genetic information, when that cell divides, that new information is passed on. So these cells are there for the lifetime of the individual. They're dividing, they're passing on the new genetic information to every new cell. So by doing it once, you have the ability over the lifetime of that individual. or to continually provide that new genetic information. And that's a very, very powerful approach. You can do that, for example, in liver cells.

So if you can introduce a gene into an older individual, into large numbers of liver cells, you've got that new gene into those liver cells. In fact, in the liver, after a certain age, those cells don't really divide very much. So you've just got a population of liver cells with the new gene in, and those liver cells are continually making the new genetic information. So again, it has the

potential to have, you know, a long-term effect. And I think that's the important thing by altering genetic information because genetic information is permanently there or it can be replicated as a cell divides, then you have the ability to produce a long-term effect through a one-time administration. This is quite closely linked to one of the more controversial aspects of gene therapies, which is their cost. They can often be hugely expensive, some of the most expensive medicines in the world. Do you think that because of this one-shot potentially curative effect, that justifies the sort of millions of dollars price tags that some of these medications have? Yeah, I mean, this is a complex subject. And, you know, when you start to see, you know, those kind of price stacks,

people, you know, obviously it gets attention. But, you know, the way you have to look at it is, I think there's a number of things. Firstly, what is the value of that therapy? You know, so rather than consider price, think about the value. What kind of impact does that treatment have compared to what is currently available? So some of these therapies, for example, are for conditions where there's no treatment available at all, and where children or individuals will die from their disease. And the only thing they currently have is, you know, supportive or palliative care. And often it can be a prolonged and rather painful process, you know, with a high impact, emotional and financial impact, both on the family and also on the healthcare system. And then

you're administering a therapy that now completely changes that individual's life. and gives them sometimes a normal quality of life. And that normal quality of life could be for a lifetime. What kind of value do ascribe to that kind of therapy? And so, you know, there have been independent assessments of these treatments. And they've, you know, independent healthcare technology assessments, you know, bodies like Nice in the UK have found these therapies to be more valuable than anything else that they have previously assessed. The other way to look at it is, is our healthcare system already provides for some of these diseases a huge amount of funding. But that's over a lifetime.

So some therapies can be very expensive, you know, hundreds of thousand pounds of, for example, a year. But you have to deliver that every year. And you may have to deliver that for 10 or 20 years. So the cumulative cost of current therapies are often more than the single cost of a gene therapy. It's just that the gene therapy has to be paid at that particular time because you're only giving it one. So, you know, there's a different model here. You know, we're used to a certain model of paying regularly, which may cost a huge amount, compared to a cost that is given one time.

And so our model of how we think about paying for medicine has to change because the kinds of medicines that we're developing has changed. Wishing you could be there live for the big game, soaking up the atmosphere in the crowd. but too often life gets busy or the price hold you back. Priceline is here to help you make it happy. With millions of deals on flights, hotels and rental cars, you can go see the game live.

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At this point it would be quite useful to bring it down to earth a bit and look at in terms of diseases that have actually been treated, what are some of the biggest successes of genetic therapies to date? I mean, this is what I think is really remarkable. You know, we're in an age now where these kinds of genetic therapists are treating diseases that we never thought could be previously treated. And so, you know, I'll just give a few examples. I mean, there are genetic diseases of the eye where people who couldn't see, are now able to see. And, you know, recently in the paper there was a lot of publicity about a gene therapy for a deafness. So children who couldn't hear could now start to hear.

There are, you know, conditions where children who wouldn't have been able to walk or kind of move their limbs properly are able to do that. Children who lost the ability to learn, to talk, to interact with their families are now able to do that and could be able to do that, you know, for a lifetime. It's not just small. changes in what can be done. These are enormous impacts upon the quality of life of individuals in lots of different areas. And I think this is just the start. And I think we're going to see many, many more of these come along. And diseases that we thought were incurable or untreatable, because we now know what the genetic information is that causes diseases. And by going

fundamentally back to that genetic information, we're going to make a profound impact upon those diseases. So, you know, I started off as a pediatrician working at Great Ormond Street Hospital in London, and I was looking after children who had genetic diseases of the immune system. So these are what we call bubble babies. And these kids, you know, because they had no immune system or no functional immune system, they couldn't fight common viruses or cold or, you know, bacteria. And so the kind of things that make give us a cough or a cold would put them into hospital and on to, a ventilator. So profound was the problem with their immune system. And so, you know, what we were able to do was to take out their bone marrow cells, introduce a working copy of the gene, and that allowed

them to grow new white cells and grow a new immune system. So the first children that I treated were treated over 20 years ago with a single administration of gene modified cells. And now those children, and now young adults, are able to live relatively normal lives, as a result of that single administration. So that's the kind of profound impact this kind of gene therapy can have. And then to kind of flip that on its head then, what are the big targets, you know, that genetic therapy hasn't cured yet,

but that everyone would say, wow, that would be absolutely incredible if we achieved that? Yeah, so up until now, we've been looking at some rare diseases. So, you know, gene defects that lead some very rare diseases. But that information has led us to think about much more common diseases, diseases that affect not just hundreds of patients, but thousands or hundreds of thousands of patients. And so, you know, I can just kind of give you a few examples.

So the most common genetic disease in the world is sickle cell anemia, which affects millions of individuals. And now there are approved gene therapies to treat sickle cell anemia. So people with sick of cell anemia don't have these painful crises, don't need blood transfusions. And so that's been approved in the US and in the EU. And that, as I say, affects hundreds of thousands and millions of individuals worldwide. We are working on a treatment for a form of inflammatory bowel disease or Crohn's disease, which again affects hundreds of thousands of individuals.

And this is for a specific genetic form of Crohn's disease. disease. And so, you know, we have some very common diseases, but within that, as our knowledge of genetic makeup of diseases improves, we know that within those common diseases, there are subsets that are due to a specific genetic condition, and we can address that genetic subset of a common disease. And I say that our program for Crohn's Zee is a very genetic subset of Crohn's disease. Now, one of the big, I mean, obviously one of the biggest, you know, health care problems that we have is dementia in old age. And we're understanding that there are certain genetic forms of dementia. And again, we can start to use the information that we've already

learned about how we can deliver genes to the brain to now start to focus on specific genetic forms of dementia as well. So this is where, as I said before, things that we thought were untreatable or uncurable. We think there are now possibilities. to be able to address those forms of diseases. Are there unique challenges to delivering treatments to the brain that you perhaps wouldn't have in other parts of the body? That's exactly right. And the brain, because our most important organ is well protected.

And it's protected by something called the blood brain barrier, which is actually designed to keep out molecules, antibodies, all kinds of things. So one of the big challenges is how do you get your new genetic information into the brain and across the blood brain barrier. One of the things we've been able to do with our gene therapy that we've developed, which is using, as I said, these blood stem cells, is that these blood stem cells, as a subsection or a proportion of these blood stem cells, have a natural ability to cross the blood brain barrier.

Some of these cells have to get across the blood brain barrier in order to protect the brain. So if you can introduce new genetic information into those blood stem cells, then you've got a vehicle or a way of trying to get that new genetic information into the brain. And so, you know, how do you use that information to then deliver these new genes to stop neurons from degenerating? And so, again, we're looking at addressing some genetic forms of dementia. It sounds like on the optimistic end of the scale, what you're describing is a future where genetic diseases are a thing of the past. Is that realistic? thick and what sort of time frame are we looking at for that? And if that's too broad,

you know, where are we going to be in five and ten years' time? As you hear about these things, we always think, oh, wow, this is going to be the solution to all of these genetic diseases. And I don't think that's going to be the case. Some will be too complex or some it might be about can you deliver to that particular cell type. So there will be some, you know, very big challenges. But I do think that more and more genetic diseases will be addressed through genetic therapies. I do think that already we're using genetic correction of certain cells to address cancers, for example. So it's not just about genetic diseases. It's about using genetic therapy to address cancers as well. So let me put it like this. I think the initial phase has been in

Rare diseases where there's a single gene that is affected, and more and more of those will become amenable to gene therapy, will be corrected by gene therapy. I think there is a path by which we're going to be able to address genetic subsections of much more common diseases as well, as we understand the genetic makeup of those diseases. I think we're going to be able to manipulate cell types, introducing genes into different cell types, to address cancers and maybe also diseases as well. So again, big areas of medicine of healthcare that are currently have limited treatment options and where the use of genetic therapies can have a profound effect. So I think that's how this will evolve. Over the next five years, I think you'll see more rare diseases

being corrected and potentially going into some of these larger indications. And who knows, you know, what happens over a 10-year timeframe. Because, you know, the technology just, evolve so quickly and we're going to get more tools in our toolbox to address more of these indications. Obviously, all hugely, hugely positive and really, really exciting time to be sort of in this field or just living, you know, with the hope that a lot of these diseases can be treated. But gene therapy and the sort of Pandora's box that you opened also comes with some ethical considerations. You almost can't have this conversation without discussing the possibilities of people designing their children's genetic code. What do you say to those sort of

critics that this perhaps has, you know, almost with the AI debate, that this could go too far and we can't kind of put it back in the box? This is, you know, a discussion or a concern that comes with almost every new type of technology. And you talked about artificial intelligence. And sometimes the technology or the science is way ahead of our ethical and social considerations. You know, the ability to do things is already there. And what we have to do as a responsible society is think about where it can be used appropriately and how we control or regulate it appropriately. So we doesn't start to cause harm or go into areas that cause, you know, social and ethical concern.

We as, you know, scientists, positions have to be able to make that information available in a transparent way. and we have to have debate and discussion about how it is appropriately regulated and what should be done and what can't be done. And that's a question for our society to determine, because there'll always be the ability to do things, but that doesn't mean to say that we should do those things. It's about what is useful for us as humanity and society, and what are the things that may well cause harm and to regulate and to police that appropriately. Finally, then, this episode, we're going to title it, The Gene Therapy Future Has It? Are we living in it right now? We are. We're definitely living in it. I mean, we now have what are, you know, standard approved medicines that are gene therapies.

So, you know, a patient, you know, with a specific disease has the ability to have a gene therapy as their medicine. in the UK, that is available on the NHS. I've got this disease, gene therapy is going to be the medicine that I'm going to have in order to correct my disease. It's already here. It's here now for, I say, a limited number of indications, but that is only going to get more and more as time goes by. And there are just so many of these in development.

So, you know, behind what's already approved are many, many gene therapies that are showing in effect in trials in patients. And so that's very, very exciting because you can already see it happening, you know, in the clinical trial research setting. And so those then need to be taken through the regulatory pathway and then get approved and then become available to standard medicines for patients. You know, when I was, you know, growing up as a medical student, you know, you're reading the textbooks and you hear about, you know, diseases and these are the medicines that are going

be available for those diseases. When the textbooks start to get written, in the future, medical students will hear about a disease and the standard treatment of that disease will be a gene therapy. It becomes part and parcel of what is our medical landscape, our clinical landscape, what patients can expend. So that was Bobby Gaspar, a professor of pediatrics and immunology at Great Ormond Street Hospital and University College London and CEO of Orchard Therapeutic. Thanks for listening to this episode of Instant Genius, brought to you by the team behind BBC Science Focus magazine, which you can find on sale now in supermarkets and newsagents up and down the country. If you enjoyed this episode, make sure to subscribe by your preferred app and leave us a review. You can, of course, also find us online at sciencefocus.com.

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