February 19, 2020

Scratched knees, smelly yogurt, and speedy wound healing

By Conor McKechnie and Dodi Axelson

Scratched knees, smelly yogurt, and speedy wound healing

So, what does yogurt have to do with wound healing? In this episode, Evelina Vågesjö from Ilya Pharma helps Conor and Dodi see the connection. It’s all about getting help from our small bacterial friends, lactic acid, and chemokines. Tune in to learn how it all connects.

DODI: I'm going to record this.... A sound that every scientist knows and loves.

CONOR: And that every patient fears.

DODI: We have snuck into the first aid room because our topic today actually might have to do with what happens in many first aid rooms around the world.

CONOR: First aid rooms are not places that you ever really want to visit. But sometimes, I guess, that just kind of happens. So, Dodi what are we talking about today?

DODI: We're going to talk about wound healing on this episode of Discovery Matters. Conor, let me paint a picture for you.

CONOR: Oh, please do.

DODI: It is summertime. You've taken your kids out to play and what do you see at a playground?

CONOR: I see like 100 000 different opportunities for injury. I'm an experienced parent. Everything there is designed to basically help me accelerate my journey to the emergency room.

DODI: Or the first aid room.

CONOR: Yeah, exactly. That's basically what you know, the first eight years of my childrens’ life was all about, it was trips to the emergency room for the weirdest reasons.

DODI: Well, me too. My son actually, we were standing there cheering him on, swinging higher and higher and higher and then he jumped…

CONOR: …and then boom.

DODI: Scratched knees, you know, wounds. These are things that we see in a playground.

CONOR: We do. We see it all the time.

DODI: And we also see, you know, parents or, or guardians with snacks in their pocket and yogurt is kind of a thing that that a lot of kids get as their snack. Right?

CONOR: They do. And then it gets spilled in the car and then that's ruined a car, like a yogurt spill.

DODI: That gets stinky later on. But we're coming around to how to connect yogurt and scratched knees or serious wounds.

CONOR: We're not just talking about like parenting being a really messy business that nobody ever tells you about. There's actually a, there's actually a connection between wounds and yogurt.

DODI: That's right. We're talking about the idea of using the body to heal itself. And we met somebody who is thinking about healing wounds, not at a playground. She's thinking on a much more serious level.

EVELINA VÅGESJÖ: I'm a very dry person. I have eczema. I get dry skin from it. I don't know it is that, but I've always been interested in skin and skin biology.

CONOR: So, who is that?

EV: I have a name that doesn't translate well in English. It's Evelina Vågesjö, so I’m from Sweden. Normally I'm presented as Evelina from Sweden.

DODI: Evelina has founded a company called Ilya Pharma.

CONOR: Ilya Pharma?

DODI: Yeah. And her whole idea, her whole team's idea, is to genetically rebuild lactic acid bacteria, the stuff that you find in yogurt and use that to produce a bodily substance, which in turn helps speed the healing process.

EV: We've set out to accelerate healing of difficult-to-heal skin wounds. That is the first indication and the second indication we work with is wounds in the gastrointestinal tract, for instance inflammatory bowel disease. And how we do this is that we have come up with a new type of biologic drug candidate that we're working with. And instead of adding a well-known protein in healing processes, we have designed the delivery system that allows for continuous delivery to the wound surface in a very cost-efficient way. And exactly how we do that, is that we actually designed lactic acid bacteria and put in a gene for a human well-known substance in healing processes. And then it is a much simpler way to work with the manufacturing part if you have your drug as lactic acid bacteria.

So, the lactic acid bacteria is then freeze-dried and then there’s storage stability and all those parts are much easier handled. And then just before use, one reconstitutes this freeze-dried small batch of bacteria and then you apply them to the wound. And when in the wound the bacteria comes to life again. There they produce this human protein, which is the chemokine and then they produce it continuously to the wound surface for about one hour. And there we have shown that this is very important for the mechanism of action and the efficacy. So, if you just give the protein at one time point, one single time point, we don't see an accelerated wound healing for instance. So, it is the close proximity to the wound surface and that we have a continuous production over a period of time, approximately one hour.

CONOR: Okay. So lactic acid for me is what builds up in the gym or just before everything starts to fail. When you're running it hurts like hell. It's, it's, it's the substance of cramp. So, how is lactic acid going to accelerate the healing here?

EV: So, then the actual effector molecule, the main effector molecule is the human protein. It is the chemokine. It's called CXCL12, the one where we worked with first. And the reason we work with this is that if you get a wound, this is upregulated directly in the skin when you get to wound. What we wanted to do to accelerate the healing was that we asked ourselves: what if we increase this level of this chemokine a bit further? Will the body then put in more efforts to heal the wound?

So very simplified, the body thinks that the wound is much larger than it really is and therefore puts more energy and resources to the healing. And then how the lactic acid comes in is that, okay, so how do we solve this? So this chemokine has a very short half-life because that's how, how the biology of chemokines is. We had to solve the delivery of it to have a prolonged delivery. Maybe it's not the straightforward way to put it into bacteria and let the bacteria deliver it, but it has turned out to be very successful and it works very well. And we see some synergistic effects with the lactic acid bacteria produced. So, looking back, we did not know all the positive synergies and aspects before when we designed this, but we have described the synergies and we're now working with them in the development forward.

DODI: We're going to step away from that playground scenario in that hypothetical situation and get a more accurate one from Evelina where she explains how Ilya Pharma's product could help change lives, if she's successful.

EV: Maybe, I am 33 years old. Uh let's say I need to have some type of surgery. It could be any type of surgery that opens a five-centimeter wound in the skin. Let's say I also have type one or type two diabetes, then I have an increased risk of wound infections, post-surgical wound infections. If I would have had that, let's say I get a wound infection and then there is a timeline of months where I need antibiotics to treat this wound infection. It is pretty long time between follow-ups, I think. So, it's not perfectly monitored this infection, it will not be. It will not also be taken into account really that I have diabetes and that therefore other, other timelines and other risks apply to me. And maybe this infection will heal. Maybe it will not.

But how I see it, if we can find the product that actually accelerates the closing of the wound, the complete closing, not only the sutures, but the complete closing of the wound, that then has two effects. One, if you have closed the skin surface, you cannot get a deep wound infection for instance, because they cannot get in. So then therefore that's one part. The other part is also that the lactic acid bacteria per se actually take space in the wound and they slightly reduce the pH. So, we know that this part is a bit, it's difficult to anti-microbial, but it inhibits the other bacteria from growing. So, the speed of healing, but also how it looks in the wound will actually prevent the risk of wound infections for instance.

CONOR: So we've talked before on Discovery Matters about CAR-T cells and delivering something that kind of educates or reprograms your body to correct what is going on and that that's delivered by a viral of a viral vector or a virus. So, this is kind of different because Evelina and Ilya Pharma are delivering a bacteria instead or, or how does it connect?

EV: It connects a bit, but this one could think that this is delivered to a body surface instead. And then one could have done it with the stem cell for instance, but that's not super smart regulatory-wise. One could have done it with another type of bacteria, but I would say that we had lactic acid bacteria easily at hand in our research. And we actually have a panel of different lactic acid bacteria. There are many different that we've tested in this. One can also see that wounds in the gastrointestinal tract and the colon mainly. I mean that is actually also a body surface.

CONOR: How is that a body surface exactly?

EV: It is an internal body surface as the same as, your eyes, your mouth and so on. So this system works very well to deliver human proteins to body surfaces where there are wounds or inflammation. But which protein you express has to be designed to how you would like the biologic effect to be for CXCL12 we have described exactly how the immune cells in the wound behave when it's delivered, both as a protein but also via this vector that is lactic acid bacteria.

CONOR: Okay. So, this product which aims to revolutionize the care of chronic wounds, we're not talking about a lotion, are we? We're talking about something that somebody would have to have administered into their body in our hospital environment. Is that right?

EV: The idea with the product is that it will be administered by healthcare professionals and we target both hospitals, which is the case for postsurgical wounds or more chronic wounds, which is the other arm we have in our wound care project. Then it is more outpatient care settings, but still then delivered by healthcare professionals. So that just a way forward and that's how this product would work.

CONOR: So, she talked about the way forward. What does it actually look like?

EV: I would like to find a good cure to accelerate healing of chronic and difficult skin wounds foremost that actually works and makes an impact on both people's lives, their relatives and, and also has benefits for the society. And I think what is starting to surface now is health economic analysis for wounds specifically. This has not been going on for so long. UK is a lead in this. We see some from Denmark and also some from the US that start to describe actually costs and follow one wound. It will solve a big economic problem. One can see that for a chronic wound for instance, how much it costs syringes between 10 000 to 30 000 US dollars.

CONOR: 10 000 to 30 000 dollars per year!?

DODI: No per wound!

EV: And some patients have their wound for years. Some have them for a couple of months. I think is very important to follow the cost per wound and also try to monitor the additional cost this will cause. So actually, chronic wounds are not only a problem in the retired population, it is also in the active workforce for instance. And those are side effects or economic side effects that happens if one has a wound, the loss of work capacity and so on. I think it's very interesting when data is building on this. Basically the ultimate, the worst case of a wound infection in a chronic wound is an amputation of a limb and then one knows that this costs around 50 000 US dollars for the first limb amputation. And one also knows that if a person has a second limb amputation, the quality of life decreases very rapidly after this. I also really like what, what's happening in the field where, where the five-year mortality is looked upon after wound infections. It actually looks much worse than for more than half of the cancer diagnoses. So, I think this is really building awareness that this is an important problem.

DODI: Ilya Pharma has come to our Testa Center in Uppsala to work in and run their tests at scale. Testa Center is a really interesting initiative that we run in collaboration with the Swedish government and funding for innovation. You've been there. Tell us a little bit about your experience at the Testa center.

CONOR: Well, it's really extraordinary. It's a facility that is open to customers and to researchers who are doing process development and working on new therapies, new ways of creating biotherapies. Whether we're talking about traditional monoclonal antibodies or any of this new zoo of modalities that we're seeing coming along. And it's a way of fostering collaboration across big industry and academia and government and small startups to really accelerate the progress of these new biotherapies to market and to patients is really, really exciting.

DODI: And it's a wonderful place to tell stories like we just did in this episode.

CONOR: It is because we see some of the real groundbreaking innovation and thinking coming from these small companies in these really interesting areas where biotech is gonna change the face of medicine as we know it.

DODI: Totally right. Thank you for listening to this episode. As we wrap up, I want to touch base a little bit on some feedback that we've been getting. So, A: thank you very, very much for being in touch and giving us feedback. B: Conor, I want to tell you exactly what some of that feedback is and it has to do with our microbiomes episode. People have been reacting to your showering habits.

CONOR: I just, you know what, I've had a few emails and a couple of tweets at me about this. I'm starting to worry about what you're hearing now.

DODI: Well, I can promise that it's still true that Conor does not have body odor. But one thing that I said in that episode was that I was going to try showering without soap and I just, I am still wallowing in the suds.

CONOR: Are you still, have you not taken the step? Try it. It's so liberating.

DODI: I guess you could say I don't have the guts.

CONOR: Very, very funny. You know the worst thing about not using soap? It’s leaving the soaps in the hotel bathrooms. They stay now.

DODI: Instead of packing them in your suitcase and bringing them home to sit on the bathroom counter for months and months and months.

CONOR: Yeah, exactly.

DODI: You know, we've also been getting ideas from listeners and thank you for those. Keep them coming.

CONOR: So, what's coming up? What have we got to look forward to?

DODI: We're going to hear some deep dives on oligonucleotides and protein A. I know those topics they just roll off the tongue, but they are super interesting in terms of discovering value to society.

CONOR: Okay. I don't even think I can say ol...ol...oligon. Is there a shorter, is there a shorter word we could?

DODI: Oligos?

CONOR: Oh, oligos! Okay. That I can handle.

DODI: So, look forward to hearing about those in future episodes. And in the meantime, tweet us, message us and rate us on the app that you are using to listen to this podcast.

CONOR: Yeah, brilliant. I tweet at @conorato.

DODI: And I'm @dodiax.

CONOR: So, get in touch, let us know what you think and rate us. We'll speak to you soon.

DODI: Thanks for listening.

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

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