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March 11, 2020

Antisense oligo therapy science podcast

By Conor McKechnie and Dodi Axelson

Making sense of antisense oligo therapy

In this episode Conor tells Dodi about 4-year-old Roy Muhrbeck who was diagnosed with spinal muscular atrophy (SMA). Learn how an oligonucleotide (oligo) therapy helps Roy and where he is today. Ionis Pharmaceuticals’ Max Moore explains the science.


DODI: Sometimes we get ahold of somebody's personal story, and it's just got to be shared. Our whole commercial organization got together not too long ago and saw a video about a patient story.

MAJA ÖDMANN: My whole life, I always wanted to have a child. When Roy finally was born in December, 2015 I felt like my life had…

DODI: It was so moving that we went and we chased it down further. And we want you, our listeners on Discovery Matters, to meet Roy and hear his story and why it is important in science.

CONOR: This is the sound of Roy and his mother Maja. Roy is four years old and he has spinal muscular atrophy, or SMA for short.

DODI: Oh, that's devastating. Kids with SMA didn't used to live for more than one year.

CONOR: Yeah, it's awful. So let's go out to the suburbs of Uppsala in Sweden and talk to Roy's parents, Maja Ödmann and Hugo Muhrbeck. And let's hear Roy’s story. It twisted, it turned. And as you listen, it becomes really clear that there's a lot to learn about the kinds of drugs that have been made in order to help people like Roy.

So four years ago, Hugo and Maja brought home their first child and like every new parent, they were excited.

DODI: Amen, do you remember those days? Terrifying, exciting…

CONOR: I do remember. Everybody tells you about the birth and all that kind of stuff. Nobody tells you about the rest of their lives and how horrifyingly difficult it is to…

DODI: …I remember actually watching my sons breathe and just like, are they inhaling AND exhaling? Isn't it amazing?

CONOR: And please don't forget to do the second part because you have to do it again and again.

DODI: Exactly! So Maja and Hugo, I guess, were like this?

CONOR: Exactly. And do you remember waking your children up just to make sure that they were alive?

DODI: Totally.

CONOR: My son's sleeping, but I'm going to wake him up. I know. It's awful and terrifying and beautiful. Anyway, Hugo and Maya brought Roy home, and after a while they started to think that maybe everything wasn't exactly how it should be.

HUGO: It felt like he was developing slow when it comes to movement and sitting up and crawling and stuff like that.

CONOR: So they took Roy to their local clinic.

HUGO: And they just said, you know, all kids are different and develop at different speeds. So yeah, we just bought it.

CONOR: Well, they realized something was very wrong when Roy couldn't really eat properly anymore. So back to the clinic they went, and this time they were told to go straight to the hospital.

HUGO: I think three doctors looked at him. And they walked out of the room and then they came back to Maja and said,

MAJA: We suspect that he might have spinal muscular atrophy.

HUGO: The first doctor said, there is no cure, because this is a genetic disease that you can’t cure. I mean, you can treat it and make things better, but you can't cure it. And I don't know if it was the same day or the next meeting with the doctor when he said, yeah, I need to tell you there is a study, where they are testing this new medicine. And at that point we said, okay, when can we join the study? And he said, no, it's too late. It's closed. They won't accept any more participants.

CONOR: After a week or so, the same doctor rang Maja and Hugo with just unbelievable news. It seemed that there was space for Roy in the clinical trial.

HUGO: That feeling was great. But then they told us that there's also a placebo group in the study. One out of three kids gets a placebo and two get the real thing. And that was kind of a weird lottery to be in. So when we started with the trial, we watched him so closely, everything he did, everything he was trying to do, and we looked at him and looked for change. Did he do that before? I don't think he did. Oh, he can move his legs. He can do that. I haven't seen that before.

MAJA: We analyzed him so closely when he came back from the room where he gets the injection. Is he sad? Does he have red eyes? Has he been crying, maybe because the syringe hurt very much? Or maybe because the injection was a real one, so that's why he's been crying. Now he's sleeping! Maybe because he's been crying so much. It's like we analyzed it.

DODI: Just so I have a good picture in my head, how is this treatment, whether it was placebo or the experimental therapy (because clinical trials have a control group)…How was that therapy administered?

CONOR: If you can imagine an infant, it's administered directly into Roy's spine. Every patient feels a little prick on their back. But no one knew who was getting the placebo and who wasn't.

MAJA: In August, I remember I was there and thinking, Oh, now he's going to meet the physiotherapist and he's going to show her that he's stronger now because of the medicine. And I remember that moment, he couldn't continue the exercises. And he couldn't breathe and it was chaotic and I was sweating so much, and he couldn't even breathe through this exercise. And I thought he would show that he's stronger. So that is how much I wanted this, how much I imagined this, and I understand that's why they have a placebo in some studies. My hope couldn't change his muscles or his DNA. But I thought he got the treatment because I wanted it, but then I understood that it was a lost race, that he didn't get it. He was only getting weaker and weaker and weaker, and we were spending more and more time at the hospital. And we noticed that he's not getting stronger, only weaker, but it took months.

DODI: So they started noticing this improvement and thinking, Oh, you know, he's getting better.

HUGO: That was just in our heads. It wasn't real.

DODI: Oh no!

CONOR: I know, but don't despair. A few months after they learned that Roy had been on the placebo all this time, the doctors came to Hugo and Maja and said,

HUGO: There is so much clinical evidence that this medicine works.

MAJA: They called us and they said, now we're going into phase 3. Now everybody, including the ones in the placebo group, will get the drug.

DODI: Phew. Oh, great.

CONOR: Yeah, but hold on. I said this story twisted and turned. It turns out that they would have to wait for two whole months for the real drug, and this of course was the two longest months of their lives.

MAJA: Those two months, it was a race against time, because I could feel and see Roy losing abilities every day. I could see, Oh, today he can't do this anymore or today he can't do that anymore. Or now he's losing something that he will not get back. He will not gain it back because that's what the doctors told us, that whatever he's losing, he will not gain back. He will only stabilize where he is.

DODI: That is excruciating. So did they get the therapy in the end?

CONOR: Well, that was a whole journey in itself.

HUGO: So we took the ambulance to the airport where we boarded the smallest propeller plane. You couldn't even stand up in it. It took us to Gothenburg because that's where this study was. This is also where we had to go every four months for the injections. It was a tough trip for all of us, but it was also kind of a journey. We had mixed emotions.

DODI: Okay. I want to hear much more about Roy, but I think we need to get some science at this point. Can you tell me a little bit more about this therapy that they'd waited so long for and traveled so far to get?

CONOR: It's an unusual type of therapy that uses something called an antisense oligonucleotide – I’ve been practicing. So it's an antisense oligonucleotide and it's better that we get the expert view to tell us some more.

MAX MOORE:   Oligonucleotides are really just short strands of DNA or RNA in our cells. They're used to regulate gene expression, but of course they can be synthetically produced as well and they're used broadly. So think about things like CRISPR, PCR, cloning, molecular probes, forensics, microarrays. They are sort of ubiquitous to genomics research. To give you an example, they're used in high school labs, so very broad based. At Ionis, we use chemically modified RNA known as antisense oligonucleotides to target RNA.

CONOR: This is Max Moore and he works with labs that make DNA or RNA strands called oligonucleotides, or oligos for short.

DODI: So these are really useful in many contexts. It's not exactly that they set out to use oligos in therapy specifically. Is that right?

MAX: Precisely. If you're living in a developed area, your life has somehow been touched by oligonucleotides. They're used in forensics, they're used in cloning, they're used in basic genomics. They might have been used in some sort of diagnosis that your doctor made, they might've been used at the laboratory during the testing. But they're used quite broadly.

At Ionis, we're talking about chemically modified RNA known as antisense oligonucleotides that bind precisely to their target RNA through Watson-Crick base pair bonding. It's something that eukaryotic cells have used for hundreds of millions of years. And depending on those chemical modifications, we can do a number of things. For example, we can downregulate proteins through an RNase H pathway. We can upregulate proteins by directing splicing, or we can simply degrade a toxic RNA. And that's just a few examples. But if we go back to the simplicity, I think the way to think about it is…the antisense oligonucleotide, which is a synthetic RNA, is the drug, and RNA is now the druggable target.

DODI: Why do we hear so little about these miracle molecules?

CONOR: The story of how Max got into working with oligos goes back all the way to 1985 when the founder Stan Crooke was working at SmithKline Beecham.

MAX: He comes into SmithKline about the time that Tagamet™ hits the market, and it’s the first billion-dollar drug. And he sees a profound change in SmithKline, appropriately so, as they’re moving more towards sales and this sort of thing. Stan is a purist in terms of research, and he sees the small molecule approach. Examples of small molecules are ibuprofen, aspirin, Lipitor™, and benzodiazepines like Valium™. And that's really what SmithKline was focusing on, that's what Tagamet is. The challenge with the small molecule approach, and it works really nicely, is: You don't learn anything from one molecule that you can apply to the next. As a matter of fact, even with one molecule, if you add or subtract a handful of atoms, you can take a compound with a therapeutic effect, that’s pretty safe, and make it to where it has no effect or even worse, make it incredibly toxic.

Stan, at the time, was thinking that what the industry really needs to pursue is something disruptive – something where you can learn from each drug that's produced and across the entire platform and have something that’s truly kind of revolutionary in nature. And he's having these introspective thoughts. At some point he goes to, I believe a symposium, and he hears about antisense oligonucleotides. I think a light bulb comes on in his head and that's when he sets off in 1987 to found Ionis.

Now what's truly interesting about this is he's taken a handful of scientists, incredibly bright people. He's working essentially out of a garage in Carlsbad where literally the labs are separated by Visqueen, you know, plastic. And he's saying, Hey, we're going to found a genomics-based company. But keep in mind that the human genome project didn't start until 1993 and didn't finish until 2003. What does that mean? It means everything. You know, this is kind of a moonshot approach. We have to build everything from the ground up. Today, for $100 you can get your dog's genome sequenced. There was nothing like that around back then. Going back to the human genome project, that was a $3 billion project that I think something like 10 to 15 different nations worked on, college students across college campuses everywhere contributed to it, a massive undertaking. And here you have just a small group of scientists saying, Oh, we're going to be a genomics-based company. So getting back to this grounds-up approach I can tell you a good example from the manufacturing perspective. I remember it was shortly after I started here 23 years ago. I was fairly new and I'm sitting in a meeting and we're talking about potential for commercializing a drug that we're working on. It's a cancer drug. And somebody's got their calculator out and they're saying, if this many people take this drug and they need this many kilograms of drug…Finally somebody speaks up and says, I don't think we're going to have enough salmon sperm to supply the market.

DODI: Did I just hear him say salmon sperm?

CONOR: He did say salmon sperm. And he started laughing to himself thinking that they were just joking.

MAX: As it turns out, we were making synthetic RNA and DNA. But we have to start with adenine, cystine, guanine, the bases of life, so to speak. At this point, they're being derived from salmon sperm. So you get the salmon sperm, you chemically digest it, you go through some separation process where you can individually separate out the bases. And then there's some chemical model iterations and modifications that occur after that. But you know, they were quite serious. You start calculating how much salmon sperm you need, and you realize you're going to wipe out an entire species, potentially a couple of biomes just to supply the market. And obviously those things aren't acceptable.

DODI: So where does Max see this field going in the next 5 to 10 years?

MAX: The field will continue to invest heavily in genomics-related tools. We'll invest in all portions of the platform. Expect to see new routes of delivery. And really what we're talking about here is increasing therapeutic index. So convenience to the patient. We're talking about more potent compounds. And what I think is really exciting personally, is Ligand-Conjugated Antisense (LICA) technology where we'll be able to direct drugs rapidly. Two of the phase 3 compounds use LICA, where we can direct the drugs to specific organs and more importantly, specific cells. So if you think about it in layman's terms, if you were to cut yourself on your finger and you didn't take good care of it or maybe you're having a wonderful vacation in the tropics and you suddenly have an infection, you're going to go to the doctor. They're going to give you an antibiotic, and you're going to have to take it for a while. And it gets distributed across your organs and in your blood and eventually a small amount of it gets to that point of infection.

If you have to take such large amounts, you're probably going to experience side effects, like intestinal discomfort, because your flora gets completely wiped out. And then you're going to have to cut your vacation short because you can't be in the sun. The list goes on and on from there. But imagine for a second, if you could take just a very small amount of that same antibiotic and when you took it, it went to the cells that were infected. So that's kind of what we're talking about with LICA technology – is being able to direct the drug exactly to its point of action.

CONOR: And for Max, this work is just fascinating. It's personal, it’s rewarding.

MAX: A lot of people will do research and they never get to see their discoveries broadly applied. But for a manufacturing person, to be able to do research in a lab and then see that actual discovery applied to a manufacturing process for a drug that's going to go into a toxicology study with animals and then immediately into human beings…That's pretty exciting stuff.

Here at Ionis we have this tagline, Sick people depend on us. I really live that and we really live that. You know, there are a few things humans share in common. At one end of the spectrum you have birth, and on the other one you have death, and everything in between gets really gray. But more than likely, unless you're just incredibly lucky, you're going to get sick. For me, the most important part of my job is knowing that I have a hand in potentially helping people that are sick.

DODI: Yeah. Max is super inspiring. He knows all of these patients that he's making a difference for, and we're learning so much here that I think we definitely need a second chapter on this type of therapy and more patients. What do you think?

CONOR: Yes, we definitely should, but first let's check back in with Roy.

HUGO: Today Roy is four years old. He's going to daycare with his assistants, and he's a happy boy. He likes to play. He just started to play Memory and he loves it. Every day, he wants to go downtown and look at trains and buses. Every day, no matter what time it is, even if it's in the middle of the night. He still can't sit up. He can lay down, and he can almost turn over to the other side. The improvement is really, really slow right now, but it is there.

MAJA: Between the phase 3 injections I could see only one thing improve, but that's because we started from zero. Roy could only move his eyes when we started. So after the first injection I could see him moving his shoulders. And then after the second I could see him lift his underarm. After the third, he was moving his head from side to side. So I could see one thing every injection in the beginning. But now he's just improving what he already gained. Like now, he's moving his head very fast. Now he's lifting the arm very strongly, but he's not lifting the upper arm. Still, he's getting stronger in another way now.

DODI: But the reality is, Roy is looking at receiving this therapy or dealing with spinal muscular atrophy for the rest of his life. And so on a future episode, we're going to meet another parent of another patient who has been receiving this therapy for five years already. And we're going to talk to the physician who is running that long-term clinical trial.

CONOR: Until then, thank you for listening. Rate us on your favorite podcast app and we'll see you next time.

DODI: Bye for now.

Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with Soundtelling. Production and music by Thomas Henley.

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