Short Wave - How Gene Therapy Helped Conner Run

Episode Date: August 5, 2020

Gene therapy has helped a 9-year-old boy regain enough muscle strength to run. If successful in others, it could change the lives of thousands of children with Duchenne muscular dystrophy. NPR's Jon Hamilton tells us about Conner and his family...and one of the scientists who helped develop the treatment, a pioneer in the field of gene therapy.See pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences.NPR Privacy Policy

You're listening to Shortwave from NPR. Connor Curran was four years old when he was diagnosed with Duchenne muscular dystrophy, a genetic disorder that was causing his muscles to waste away. By the time Connor was in the first grade, his parents, Jessica and Christopher Curran, could see that their son was struggling. He pulled himself up the stairs. He would make it past four stairs and he couldn't do the rest. He could not last a full day in school.

the teacher would say we let him take a little nap in the classroom, and I'm thinking, what? Jessica remembers the advice one doctor offered the family. Take your son home, love him, take him on trips while he's walking, give him a good life, and enjoy him because there's really not many options right now. But they weren't ready to give up hope. About a year after Connor's diagnosis, the Curran's heard that scientists were working on a treatment, an experimental gene-thens. therapy that might be able to help. The concept is very simple. You're missing a gene, so you're putting it back. Today in the show, NPR science correspondent John Hamilton, tells us about the decades-long

journey to treat muscular dystrophy, the tenacious scientist, Jude Simalski, who pushed to make gene therapy a reality and how his work has helped Connor Curran not just walk again, but run. Maddie Safai here with NPR science correspondent John Hamilton. Hi, John. Hi, Maddie. So, John, where would you like to begin? I think we should start with the scientist. Okay, let's do it. Okay. So obviously, many, many scientists have worked to understand this disorder. But today we're going to focus on Jude Somolsky. Back in 1984, Jude Simulski was still a graduate student at the University of Florida, and he was part of this team that cloned a virus called

AAV. And those are a group of viruses that can infect people, but they don't cause diseases. Yeah, I mean, I remember first learning about this in grad school, John. That discovery was a big deal because basically we can turn these viruses into tools. And that's because viruses on their own are pros at getting into our cells and getting up close and personal with our DNA, which is exactly where you need to get to treat a lot of genetic disorders at their source. Exactly. And Simulski was one of the scientists who figured that out. So as you know, these viruses have just revolutionized gene therapy. Right. And after Simulski and his team cloned A.A.V, they wanted to try to use the virus to treat Duchenne muscular dystrophy. That's the genetic disorder you were talking about earlier. Got it. So a lot of these therapies work by kind of targeting a gene or genes that are the root of a disorder. So what's the deal with Duchenne muscular dystrophy, John? Kids who have Duchenne lack a functional version of a gene called DMD. And this gene makes a protein called dystrophin that helps muscles stay healthy. Got it. Okay. The idea is, if the problem is that someone lacks a working gene, you could just give them a working copy of that gene. And what Samolsky wanted to do was pack some of the genetic code from a dystrophin gene inside a A.

Right. And then once the virus got into the body, it would infect muscle cells and then that faulty code. is replaced with a functional version. Right. Smolski says AV, this harmless virus, would work as a kind of transportation service. It's a molecular FedEx truck. It carries a genetic payload, and it's delivering it to its target. Right. But it turns out delivering a gene is a little bit harder than delivering a package.

And the dystrophin gene is especially challenging. One reason is its size. The AAV virus, our FedEx truck, is incredibly tiny, even among viruses. It's so small you need an electron microscope just to see it. And then you have the dystrophin gene, which is huge. It's the largest known human gene. It contains about 500 times more genetic code than AAV. So fitting that specific gene into that specific virus would be like trying to get a football stadium into a FedEx truck. Something like that, yeah. And Simolski has some other challenges, too.

One is that Duchenne affects billions of muscle cells all over the body. So this AAV delivery truck would have to be programmed to find all of these cells, recognize them, and then infect them with this new genetic code. And Samolsky spent like 15 years tackling these challenges. He was going along. He was making progress, he said, but it was coming one small step at a time. This was very challenging. It was the Mount Everest, the gene therapy community,

and each one of these steps was like setting up base camp. But then in 1999, Somolsky's work, for that matter, all gene therapy research pretty much came to a stop. The reason was that a teenager named Jesse Gelsinger had died in the gene therapy experiment. Right. I mean, I remember learning about that in graduate school in genetics. It was horrible. It was really sad. The experiment he was part of had nothing to do with muscular dystrophy or the AAV virus, nothing to do with Simolski's work, but it didn't matter. Gene therapy trials were postponed or abandoned, investors disappeared, and so did research funding. It stopped everything. Everyone got super cautious. Everyone except the muscular dystrophy

association. You know, that's the Jerry Lewis Telethon people. They continued to push for the advancement of gene therapy. Yeah, and I mean, that makes sense, right, John? I mean, there are a lot of families that wanted to see this research continue, despite the risks that come with, you know, any new therapy. Absolutely. And in fact, it's because of the Muscular Distrophy Association that Smolski was able to keep his work moving forward pretty quickly. He did have some funding already from the MDA. But as other sources dried up, he approached the association about a grant. And that's when his career took this big turn. Because the MDA didn't just want to fund more research. They wanted something that would help kids with muscular dystrophy. So Mulski told me that

He was like a few minutes into the conversation and they told him, Jude, we loved the work. We loved the research, but we're tired of funding academics that just publish a paper. We need something to turn into a drug. I don't know how I feel about that, John, but I get it. So, you know, no pressure, I guess. So did he take them up on it? He did.

In 2001, Samolsky and a small team of people created a company called Asclepios Biopharmaceutical, or Ask Bio. The company's goal was to develop an actual treatment for Duchenne muscular dystrophy. So fast forward to today. Samulski and his team were able to figure out the last piece of this puzzle. They managed to create an abridged version of the gene, one that's small enough to fit inside their viral FedEx truck. So basically they made a version of the gene that was smaller but could still do its job.

Right. Or at least he could do part of the job. The idea was to get cells to make at least enough dystrophen so that they would stay healthy. Okay, so once they had this condensed gene package, how did they test if it worked, like, if the virus could actually deliver this healthy gene? It was pretty much the usual process. They tried it in test tubes, then in mice, then in larger animals. In this case, they used golden retrievers with a genetic mutation that's a lot like the ones that kids with Duchen have. You know, typically these dogs can't stand on their hind legs because they've lost so much muscle, and they usually don't live more than about a year. but the dogs who got Samolsky's gene therapy, they did much better.

And once the company got to that point, they actually sold the treatment to the drug company Pfizer. A few years later, voila, you know, Pfizer began human clinical trials. And guess who was the first patient? Oh, Connor. Connor, Curran, the little guy we heard about earlier in the show. Yep. Connor's mom, Jessica, had actually seen videos of the dogs, those golden retrievers that had received this genetic therapy. And for her, this was just a huge.

huge moment. They were able to run and jump. We saw this, we saw this with our own eyes. And we, we just thought, oh, gosh, if one day Connor could get a chance to get something like this, it just gave us so much hope. Yeah, I mean, that must have been incredible, John, but like also kind of scary, right, for their son to be the first human to go through this trial. Yeah, really scary. And Jessica told me that as that day was approaching the day of treatment, that she was having some reservations. I looked at my husband and I said, Chris, are we doing the right thing for Connor? And he said, we need to be in this together, Jess. And let's think about the alternative.

And the alternative is death. Yeah. Connor, on the other hand, I asked him about it. And he was pretty much unfazed. What he told me was that after all the tests he'd been through to, like, get into the trial, actually getting this stuff, this stuff he calls muscle juice, it was really easy. I put an heel in my arm for two hours. So when was this that Connor got his muscle juice and like, how is he doing now?

That was back in 2018 and the treatment worked very quickly. Within three weeks, he was running up the stairs. Oh, my God. John, could you imagine? Oh, my gosh. That's so excited. For a mom. And Connor, too, was kind of blown away.

He says he kept improving. I can run faster. I stairs better and I can walk through Goldbergs at some bagel shop. And it's more than two miles. And I couldn't do that before. I mean, I love that so much, John. I know. He's a really a cute kid.

So, John, does this treatment help undo the damage that the disorder has already caused? Or does it just like stop it from progressing where it is at that point? I think it's more the latter. This treatment appears to stop the disorder from progressing. And with Connor, it has stopped his muscles from deteriorating anymore, at least at the moment. He's also stronger because the muscle cells that he has left are healthier. But it's not clear how long his new genes will last. It's also not clear whether Connor could safely get a second treatment.

And there have been some other issues as well. A few days after he got treatment, Connor developed a fever. He stopped eating. And it turns out that's a common response to this kind of therapy. So Samulski and his team, they've been working on what they hope will be a fix for that. And, you know, Conner's improvement, I mean, I mean, I don't know, John, it sounds really promising, yeah, and it's a huge deal. I mean, this has been decades in the making, and this disorder affects thousands of kids, right?

Right. I mean, this is a story that began in 1984. That's a little bit ago. And I started reporting about that time, and I remember as the genes for Duchenne and other places were discovered, I remember all the talk about how well treatments were right around the corner because now we know what the bad gene is and we're going to fix it with a good gene. But it is really only, now that you're starting to see studies like this one. And I should say that now this Duchenne treatment has been tested on nine kids and Pfizer is planning a much larger study later this year. It is only now that this is finally seeming to be real. Yeah. Wow. All right. Well, we will keep an eye on this, John. We appreciate you. Thank you so much for bringing us this story today.

You're welcome, Maddie. Thanks for having me. This episode was produced by Abby Wendell and edited by Viet Leigh. Burley McCoy Check the Facts. I'm Maddie Safia. Thanks for listening to shortwave from NPR.