In the fall of two thousand seven, a twenty three year old man went to see a doctor in Padua, sitting near Venice in the north of Italy. He had a blood clot in his leg. The whole case was unusual. The man was young and healthy, and he didn't take drugs. It turns out that the patient, whose name is still a secret, had a genetic mutation in his d N A somebody so rare that it had actually never been seen before. Yeah, it made a big impression on the
doctor who saw him that day. Dr Paolo Simione I immediately realized the importance of this same mutation in a completely different context. They therapy. Gene therapy is an emerging area of medicine generating a lot of excitement right now. If it works, it could transform the lives of people who suffer from thousands of different conditions caused by tiny abnormalities in their d NA. It turns out that young man in Padua had walked into Dr Simone's office with
a possible cure. You see, his blood clotted too easily. A protein responsible for blood clotting was too active or supercharged. But about twenty six thousand people around the world suffer from an opposite condition, hemophilia B. When most of us bleed are blood naturally forms a clot so the bleeding stops.
But this natural mechanism doesn't happen in people with severe hem ophelia, which means that even with a relatively minor injury, people with this condition could suffer from serious internal bleeding. He was Betty, Betty Vitty excited by this fact that
this might be a real treatment for remostly. Indeed, hemophilia B, the disease that famously plagued European royal families for generations thanks to Paulo Simyonis discovery back in two thousand and seven, scientists have been working on a new treatment that is now being tested on patients with him ophilia B. And unlike the frequent hospital visits and infusions patients have had to put up with their whole lives, this is potentially
a one time treatment. Hi. I'm Brad Stone and I'm Donnyloomfield, and this week on Decrypted, we're taking you to the frontiers of science where we're starting to see the first effective gene therapies, treatments that could rewrite the lives of people living with genetic disease. Will follow one patient, in particular, j Con Duros, on his journey through an experimental trial
to effectively get rid of his hemophilia. The potential cures are setting the stage to one day upset the ten billion dollar hemophilia market and even the gigantic billion dollar rare disease market dominated by genetic conditions like hemophilia. A small number of companies are on the brink of transform into space. Will go inside the lab at one such startup to explain the biotech breakthrough and how it's changed Jay's life. Plus we'll take a look at the challenging
road ahead. So, Donnie, you're a biotech reporter. In simple terms, let's explain to our listeners and frankly to me, what gene therapy actually is. Genes are the underlying code of life. Humans have about twenty thou genes in their DNA, and the different genes they produce different kinds of proteins, which turn out into all different kind of characteristics that show up in our body, like our hair color, eye color,
or how likely we are to get breast cancer. By the same token, they can cause real problems when they're messed up. Or when we have a bad mutation or body. And sometimes people might be missing a particular gene, or they might have a mutation that means their bodies don't operate normally. So the ideas gene therapy and fix it.
Are you replacing a gene. The idea is, let's give these people a good gene, properly functioning gene that allows them to effortlessly start producing the proteins that they need from having the good gene in their body. So, being a tech guy, I think about this like altering a little piece of computer code to make make the computer function differently. Is that's sort of right. So in this case, it's not altering a code, it's giving people a new code.
And when you give people that new code, they can run that, and you can think about a cell almost like running a piece of software which ultimately turns into these proteins. Of course, there is a big difference. You can't just try out whatever kind of code you want on people because even a little change can make a huge difference. They could hurt someone, that could kill someone. You have to be super cautious. You know exactly what
different code you're putting into someone's body. So this concept of gene therapy has been around for a while now, right, Yeah, but it has gone mainstream. So far, there have been very few large trials and people, and most studies so far haven't gone right, they've failed. But recently these treatments have started making the way of real patients Like Jay. As soon as I had any knowledge of anything, I knew that I had humophilia because um it had been
diagnosed before, like by the time I was born. So I actually techniques beak of not missing the factory nine. The factory nine my body creates is creates a lot of it, but it's misshapen. It doesn't work properly. Factor nine. We're going to hear a lot more about that today. It's a protein found in our blood if we get a cut and start bleeding, Factory nine is a key part of the system in our bodies that stops the bleeding. The fact that Jay's genes don't produce a functioning version
of this protein has had a major impact on this life. Yeah. Jay grew up in Canada, Montreal and Toronto. He says, the childhood was pretty normal Montre. All days were just your typical sixties seventy family life. I guess the father working, mother homemaking, and kids doing what kids do. But my very earliest memories are definitely the Volkswagen Peace Love vans and uh that's sixties vibe. I think it's in my soul for sure about it. For Jay, everything was normal
except a hemophilia. How would you explain him afiliate to people if you did believe it or not. I've never breach approached the topic. For me personally, I've avoided any talk about it or to the point of leaving a room if it's the discussions that got that way. As a kid, Jay's friends would play hockey in the street or wrestle for fun. But because of Jay's hemophilia, what would have been regular scray and bruises for one of his friends would mean Jay's mother rushing into the hospital.
Those things, even as a kid, were terrifying to me. Those things, would, you know, end up putting you out of commission kind of for you know, going to school for a couple of weeks at a time or even more, and then you'd be limping for another month recovering. So so since you'd know what's gonna happen, those kind of injuries were, Yeah, they get head towards being kind of terrifying. Today, Jay is fifty three years old and he isn't playing
hockey in the streets anymore. Umphilia has become something he learned to live with. He and his wife Yolanta run a bakery called Nougat in Kitchener, Ontario. Hi, Lacy, it is newgat bakery, J speaking, can I put it in order for tomorrow? Almonds blenched meal, T pounds one box almond. For years, Jay has managed a hemophilia with a portable kit keeps with him so we can give himself an infusion of the factor nine protein when he's worried about
a bleed. Despite that, a single bump, even if properly treated, could still swell up with internal bleeding and turn into a medical nightmare. For example, but in just a couple of years ago, I ended up. I was shoveling snow and this shovel cut the the ashphalts and the tip of the shovel, which rotated the handle sideways into my thigh. An everyday incident like this could be really dangerous for Jay.
Knew that was going to cause a bruise for sure, so I actually went home and getting myself a treatment right away. That's a factor nine infusion. Kid. Jay keeps at home, and then ended up being in the hospital for ten days and I was kind of on on steady dose factor nine treatment for the next month. I think, you know doctor's orders, and um, well it's on crutches.
I think for another three weeks after I got to the hospital, and then on a cane and for another three months, and I think there was another three months after that before you'd say I was back to the shape I was in before. I just can't imagine how disruptive to his life hemophilia has been. I would imagine Donnie that he he really leapt at the opportunity when doctors told him, uh, they could cure as hemophilia. Well,
I don't think anyone was promising a cure. But a year ago Jay's doctor did tell him about an experimental trial with a company called Spark Therapeutics, and they're based in Philadelphia. The goal of the trial seemed outlandish. Spark was testing a new kind of therapy, like you said, that would require one visit to the hospital and maybe after just one visit, Jay would see the symptoms of
his hemophilia start to disappear. Are you telling me that you can have a disease your whole life because of so much drama and you have to have these injections. They come with their own risks of infection of you know, viruses. But all of a sudden, you can walk into some buildings, sit in a chair, have someone put an intravenous need on you for maybe an hour forty five minutes to an hour, and drip a clear bag of liquid into you and that's it. Pulled the needle out and go home.
After talking over with his wife, he designed to sign up and we said down and we talked about it, and I thought it was a great idea. Uh, there are no huge side effects on that. I'm like, you have nothing to lose. The word that comes into my mind, I don't want to even say it, but but you could say it's a it's a joke. The company behind
the trial was called Spark Therapeutics. The company has been around for four years and was born when a man called Steve Altruler, then the CEO of the Children's Hospital of Philadelphia, asked a consultant, Jeff Marazzo, to come to the hospital and see did any of the hospital's research of commercial potential. And I ended up agreeing with Steve that I would spend about three months from in the halls of the Children's Hospital Philadelphia meeting with scientists and
clinicians and people even working on health information technology. That's Jeff, who's now the CEO a Spark. And one of the last conversations I had was with a woman named Dr Katherine High. My name is Dr Cathy High, and I'm the president and chief Scientific officer of Spark Therapeutics. And our one hour conversation, which I had scheduled with her, ended up going about seven hours, and as they say, the rest is history. As it turns out, Jeff's timing
couldn't have been better. I was getting cold calls from investors in my office and I didn't want to talk to investors. I wanted to do my work. And as I was sitting there talking to him, I was thinking, Wow, if somebody like this were involved, he could take those calls. Donny, you went to go meet Jeff and Cathy in Philadelphia the other week, right, Yeah. So, Sparks Labs and offices are in the University of Pennsylvania, medical building. It's a
swanky tower of glass and steel. The bottles sit in the roller rack, and then there are rulers here, which turned it around. Okay. Kathy has been doing research in this area for years, not just in gene therapies, but
in he ma ophelia specifically. Her earliest projects were looking into the proteins that make blood clotting possible, and she helped guide patients through the nineties, which was a devastating time when most team ophelia patients in the US contracted HIV because the factor therapy became infected with the virus
was very intense term. We uh started to evaluate all the people in the clinic and it turned out that nearly everyone was positive, but we didn't know what it meant, and the and the virologists didn't know what it meant either. My first thoughts were, um, I don't remember too much because it's very is a panicky feeling because all of a sudden, here in this a group of people who
were um being hunted down by this virus. Many of your visions died, many of many of my patients died during that time in the nineties and early two thousand's Cathy was involved in some of the very first hemophilia gene therapy trials. How did those therapies go well? Early on, some of the issues was where to actually try and deliver the gene. So Cathy tried to deliver the gene to muff soul, but it just kept making factor nine but it didn't get into the blood, so that wasn't helpful.
And then they tried to get it into the liver, which is where they ended up going. But when they did that, the immune system responded. Were their negative side effects for the patients that were in those trials not significantly. So far these mafiliate trials have been really saved. So walk us through how this current trial works. What exactly
is the treatment sparks testing. The basic idea here is you want to deliver a gene, which you can think of as like an instruction manual, to the right cells that they can make the right protein. And they do that all by needing to start with a transportation device. And in this case, they take a virus, which sounds really scared. The virus does not sound like something you want in your body. Yeah, that's right. But what they
did was they found a harmless one. They found these naturally occurring harmless viruses, and you can think of them like you know biological transportation system. The idea is that they have this factory nine gene in them. They swarm into the body, their billions of them, they swim him through the blood, and their designs that they're gonna laser in and hone in on those liver cells, which is kind of the body's factory from making things. Is it
too early right now to draw any conclusions about sparks trial. Well, they've actually had fairly encouraging results. It is small, but they've shown that in ten people they can create pretty high levels of fact or nine and that's the clotting thing that that these people need. And what they've been able to find was that nine out of ten people haven't had any bleeds since they took this therapy. Is Cathy confident that this will work? She is pretty confident.
She told me that, you know, if you can do organ transplantation, she doesn't know why you can't do gene transplantation too. But there have been years of hard work and setbacks to get to this point. To be fair, there were many gene therapy trials in the decade between and two thousand and nine, and about as many failures. A young man, Jesse Gelsinger, died in once a trial run by a colleague of Kathy's at penn What do I remember when I found out about the death of
Jesse Gelsinger? I do remember Kathy couldn't have known at the time, but Jesse's death would upend the gene therapy field for a generation. Suddenly investors and pharmaceutical companies didn't want to touch this controversial field. Because I had been to speak the night before at the Hemophilia Association of New Jersey and I had been talking about the work that we were doing in gene therapy. And the next morning, the director of the hemp Association of New Jersey called
me because it was in the newspaper. It was a shock. Interesting. Jay says he actually takes comfort in the fact that SPARK is associated with the University of Pennsylvania, where Jesse died. If if there's ever a bunch of people to go with, it's the people who um got surprised in the past and learned the hardest lessons. The patient's taking part in Kathy's gene therapy studies were safe, but for years her
research kept running into a different problem. The body's natural immune system would detect the cells carrying the new genes and wipe them out. Why did they do that? Did they identify it as a pathogen? Yeah, So what happened was that they found out that when you put in these virus like particles, maybe unsurprisingly, the body react. When we get the flu or we get some other kind of virus, our body will respond and it will see
this as a potential threat. So the immune system came back, took out all those cells, left everything alone, else alone, and thought, hey, I did a great job on this. So it doesn't sound like that's what Kathy was hoping for. No, but then there was a breakthrough. Let's go back to that doctor in Patro Italy. We heard at the beginning of the show. The doctor had found a patient with a random mutation in the gene that makes the protein factorne.
This mutation is really the tiniest change, a single letter of the genome mutated changed from a g d n A. That tiny change meets factor nine protein way more effective
than normal. We still don't fully understand why, and that sounds like a potential game changer for someone like j with hemophilia B because the supercharge protein is more effective than normal, you need less of it, and having a smaller amount of gene therapy product those little things that are derived from viruses entering the body, that means there's less chance of triggering the immune system to attack the foreign elements, which is what killed the cells in Cathy's
earlier trials. So I can't wait to hear did it work. So far, it's encouraging. Eat. Out of the ten men who have been infused in this study have not had an immune response, so two of them did. But Spark thinks that can basically control that kind of immune response, and it's used steroids to try and tamp down the body's immune system, which has worked out pretty well for at least one of those patients. The other one is
still producing a pretty steady amount of factor nine. Okay, so far we've learned about this new therapy from a company called Spark to treat people with hemophilia. We've learned it's been pretty effective in the very early tests, and it gets around some roadblocks that have held back other gene therapies. So, Donnie, what's next so to move the therapy to a broader group of patients, Spark and its partner, the pharmaceutical giant Fightser will have to test it in
final stage studies, and they're called Phase three. Sparks CEO Jeff Mrazzo says it's now in Fightser's hands as to
when that trial will begin this quarter. We are also conducting a meeting with the FDA under what's called a breakthrough Therapy designation, which we received for there are human fill a B product candidate UM and those discussions, as well as subsequent internal discussions with Fish will that they will to me determine what steps they want to take for those bigger and longer trials will be necessary to make sure that the therapy works on a larger scale,
that it's safe, and that it will actually continue lasting. So this is not a done deal, no, not by any means. Tons of therapies that go into these kind of trials can still fail to show widespread success or there could be some kind of dangerous sun effect that didn't show up before. So I'm really curious, Donnie, if this shows promise with with hemophilia B as as seems to be showing what kind of other diseases can we address with gene therapy? Yeah, so Spark is actually working
right now. They've finished a phase three study looking at this rare form of blindness that's caused by a genetic defect, and they're actually moving towards trying to get that approved by the FDA. And there are other companies that are working on things like sickle cell disease. UM, there's a small group in China that's working on certain forms of cancer. Are there any ethical concerns that have slowed down the
adoption of these techniques? I mean questions about whether we are you know, tinkering with uh, you know, mother nature or or the design of our bodies. Well, I think in this case, it's not such an ethical concern. For one thing, you're not changing people's genes. You're giving them a new one, and you're giving them one that will help them live just a healthier and better life. And in a sense, we're already tinkering with mother nature when we're giving people fact or nine, which is part of
what's keeping them align in the first place. So just to be clear, they don't they can't pass on the new gene as if it was their their original gene, right, they don't. They doesn't. This treatment doesn't change their genetic makeup. Yeah, that's right. So the basic idea here is it doesn't incorporate, It doesn't get into the the rest of the genome. It's not like it's going into any of the cells that like sperm or egg that would eventually get passed down. Okay,
I got it, so um obviously and decrypted. We we deal with businesses and the technologies effect on businesses. So obviously treating hemophilia is a large lucrative market. What what do these gene therapies mean for healthcare and the businesses that are pursuing these kinds of cures. There are a number of companies like Shire and Nova Nordisk and Fiser itself, which makes a ton of money from selling therapies to hemophilia patients, and those therapies do a lot of good.
But of course, if you had a gene therapy that would be a one time shot cure, then they would be losing a lot of market share. But it's an interesting point that they could end up undermining their own businesses. Yeah, I mean I think that that's how these companies like to think about these things where you know they want to make the next generation, and in this case, the next generation is really the hope is a one time cure.
But I think that it's fair to say we're not there yet and they're still planning on making billions of dollars from hum ahiliate patients for the foreseeable future. Are are there any other gene therapies like this that are close to being commercialized? Yeah? So pharm a giant Glaxow smith Klin actually has a gene therapy on the market now in Europe for um a super rare disease called bubble boy disease. That's the kind of common name for it. It's only approved in Europe and it costs more than
six thousand dollars. But the idea is that it's a one time shot that could replace an enzyme therapy that costs like three dollars a year. So how excited should we be? Well, I think the science is super cool and it's super exciting and we are seeing results, but we shouldn't get ahead of ourselves either. We're still in the early days here, and even though there is at least you know, one patient that's out more than a year with this spark gene therapy. That's seeing it work
for them. We still need to see what the long term effects are and how could work in other diseases. And I would imagine they're some regulatory hurdles as well. Yeah, I mean, of course they're going to have to succeed in their final stage study, which is a real difficult hurl to get over, and of course when you're working with regulators, you know there's a big process ahead of them.
But the hope is that for a rare disease, those things can move quickly and if they really prove that they work, that this thing can move forward before we wrap up or show today. What are Jay and his wife you Alanta, up to now? So when I met them in Philadelphia, Jay was about to have his appointment.
He was going to find out how much factor nine was actually being active in his body, and they found out the next day that he had normal factor nine activity, which maybe doesn't sound great, but for someone like Jay, that's pretty amazing, and that's somewhere where you can really have a basically completely normal life. And it's showing. I mean, they're feeling a lot more free and Jay even feels
a little reckless. Here's his wife Filanta, Because we always traveled with the with the package with the act or nine just in case if something happens every time when we were traveling, and this time it was the first time when he said maybe I should not take it. That's a huge change. That's like hundred eighty degree change degrees change in his behavior by saying that it's generally stupid. But we only have so much space in our luggage.
So I was thinking, well, if we're going to New York in a few days, maybe you wanted to need some more space for her shopping. And from scientific point of view, yes, definitely, it was interesting. It was something and I said, okay, I have a GMO husband now. And that's it for this week's episode of Decrypted. Thanks for listening. We love to hear what you thought of this episode. Record a voice message and send it to us at Decrypted at Bloomberg dot net or I'm on
Twitter at Donnie Bloomfield and I'm at brad Stone. If you haven't already, please subscribe to our show on iTunes or wherever you get your podcasts and leave us a rating and a review. It really helps more listeners Finder show. This episode was produced by Pio Gukari, Liz Smith, and Magnus and Rickson. A special thanks to our reporter Shelley Hagen for help with today's show. Alc McCabe is head of Bloomberg Podcast. We'll see you next week.