MADDIE SOFIA, BYLINE: You're listening to SHORT WAVE...
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SOFIA: ...From NPR.
EMILY KWONG, HOST:
Hey, SHORT WAVErs, Emily Kwong here. So today we're going to talk about finding a treatment for a genetic disorder called Fragile X syndrome, right, Jon?
JON HAMILTON, BYLINE: Right.
KWONG: So as our resident brain correspondent here on the Science Desk, you've been following this story for a decade.
HAMILTON: Yeah, I started reporting on Fragile X way back when it first looked like scientists might have a drug that could treat the disorder. And for people who may not have been following the story as closely as I have, I should probably mention that Fragile X is an inherited disorder that's caused by mutations to one particular gene on the X chromosome.
KWONG: Right. That's why it's called Fragile X.
HAMILTON: Exactly. These mutations affect brain development, so they can cause lots of different problems. The most common one is intellectual disabilities. Another one is autism. But people with the disorder can also have anxiety or hyperactivity, even seizures.
KWONG: Yeah. So Fragile X syndrome can affect people in a lot of different ways. And how disabling can this syndrome be?
HAMILTON: It varies a lot, depending on the exact mutation.
HAMILTON: But a lot of people with the syndrome have pretty limited ability to use language and really struggle to learn new things. Many can't live on their own or even do basic daily tasks. But I didn't really understand what the disorder was like until 2008. That's when I got to spend some time with a teenager named Andy Tranfaglia and his family in Massachusetts. Andy was 19 at the time. And here's a recording I made one afternoon in their kitchen.
KATIE CLAPP: Andy, why don't you come in and decide? What's that?
MICHAEL TRANFAGLIA: That's salami.
CLAPP: The salami.
M TRANFAGLIA: I already gave you salami.
CLAPP: Dad got you salami.
M TRANFAGLIA: It's already over there.
CLAPP: See? And what are you going to have to drink - orange juice?
ANDY TRANFAGLIA: Yeah.
CLAPP: Orange juice.
KWONG: Yeah, so Andy isn't speaking very much.
HAMILTON: Not back then. He had a lot of other problems - anxiety, he had the seizures, repetitive behaviors. You know, he would spend hours just packing and unpacking videotapes and DVDs, or he would watch the same part of a video over and over. But by the time I met Andy, though, his parents had already spent more than a decade running a foundation to find a treatment for Fragile X. And a recent study suggests they may have finally found one. If this treatment pans out, it will be a really big deal in the Fragile X world.
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KWONG: Today on SHORT WAVE, Jon Hamilton and I discuss how one family helped scientists take on this genetic disorder...
HAMILTON: ...And how a string of unsuccessful efforts to treat Fragile X eventually led to a big step forward.
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KWONG: So, Jon, I want to know a bit more about Fragile X syndrome. This is a genetic condition, and I'm wondering, how common is it?
HAMILTON: It affects about 1 in every 4,000 males and a smaller proportion of females. The sex difference is because females have two X chromosomes, one from each parent. That means they can have one X chromosome that is fine, even if the other one is damaged. So...
KWONG: Got it.
HAMILTON: ...Fragile X is rare, but it's still the leading inherited cause of autism and intellectual disabilities. Down syndrome, of course, is also genetic, and it's more common, but Down syndrome is not usually passed from one generation to the next, the way Fragile X is.
KWONG: All right. And earlier, you were talking, Jon, about Andy's family trying to find a treatment for his Fragile X. Tell me about them.
HAMILTON: Yeah, I was talking about Andy Tranfaglia and his parents. His dad is Michael Tranfaglia, who was both a scientist and a psychiatrist. His mom is Katie Clapp, who was a computer scientist and later turned out to be really good at raising money. And together, they were able to get some really good researchers interested in Fragile X. In 1994, Andy's parents, along with another parent of a child with Fragile X, created something called the FRAXA Research Foundation. The idea was to fund research that would lead to a treatment or a cure.
KWONG: Wow. OK.
HAMILTON: Yeah. So I talked to Katie Clapp in 2008. She told me what she and her husband were hoping the research might do for Andy.
CLAPP: We're not expecting a miracle or to make up for his 19 years of development. But if we can watch improvement happen, that's a dream.
KWONG: Wow. But actually coming up with a treatment - it does sound really optimistic.
HAMILTON: Yeah, it was. But they are both incredibly tenacious people, and they had some things going for them. One of them is a brain scientist at MIT named Mark Bear. He started working with the foundation when it was just getting started. So flash forward to 2014, and Bear has actually come up with a strategy to treat Fragile X. I talked to him about it at the time. He told me about his research showing that Fragile X affects a system that helps regulate the way connections are made in the brain. He says this sort of regulation is a bit like how you keep a car going the right speed.
MARK BEAR: You really need both the accelerator and the brake to properly function. And in the case of Fragile X, it's like the brakes are missing. So even tapping the accelerator can have the car careening out of control. And a way to correct that is to take your foot off the gas.
KWONG: So basically, keep the car in control by never letting it accelerate in the first place.
HAMILTON: Pretty much. And Bear had helped develop a drug that was able to do that in mice.
KWONG: Which is great for the mice, but could those results be replicated in people?
HAMILTON: Andy was actually part of a clinical trial of this drug. He was 25 by this time, and when I visited his family the second time, he was definitely more verbal than he had been six years earlier.
HAMILTON: He was a lot better at doing things like asking for mango juice.
A TRANFAGLIA: Mango juice.
CLAPP: Andy, can you pour it in your cup, please?
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CLAPP: OK, got to stop.
A TRANFAGLIA: Stop.
KWONG: Yeah. You can definitely hear him talking more and doing his thing. And do you think it was the drug that helped Andy, or is it just that he has learned to speak more as he's gotten older?
HAMILTON: Well, his parents thought it was both. But when the study results came in, the research showed that there wasn't much benefit overall. And that same year, another promising drug for Fragile X also failed in a clinical trial.
KWONG: Oh, wow. That must have been really tough for all the loved ones of people with Fragile X.
HAMILTON: It was brutal for the entire Fragile X community. But Katie Clapp and Michael Tranfaglia - they just kept going. The foundation started funding other approaches to fixing the problem, and that eventually put them in touch with this little company called Tetra Therapeutics.
HAMILTON: So Tetra was working on a drug for Alzheimer's disease. And one of the things research funded by the FRAXA Research Foundation had shown was that Alzheimer's and Fragile X have something in common. Both conditions seem to disrupt a substance that helps transmit messages inside cells. The substance is called cyclic AMP, and the scientists who discovered it got the Nobel Prize way back in 2000.
KWONG: Casual Nobel Prize reference - OK, OK.
HAMILTON: Right, right. So you have little Tetra Therapeutics, and they had a potential Alzheimer's drug that worked by manipulating cyclic AMP. The company's founder, a guy named Mark Gurney, had this kind of epiphany.
MARK GURNEY: So we thought there was a strong possibility that this mechanism of our drug might be effective in Fragile X.
KWONG: Yeah. So did they start by testing it out in mice?
HAMILTON: They did. And it reversed some of the brain problems caused by Fragile X mutations.
KWONG: Yeah, more good news for mice, but I'm more interested in what it can do for people like Andy. What happened there?
HAMILTON: Well, of course, that's what everybody wanted to know. And in 2021, we got at least part of the answer from this study that was published in Nature Medicine.
HAMILTON: So Gurney and a team of scientists gave the drug to 30 adult males with Fragile X syndrome. And after just 12 weeks on the drug, cognitive tests showed that their language and their learning had improved. So Gurney used a range of tests to measure the amount of improvement, but he told me that the change could translate into something like a 10-point increase in IQ.
KWONG: And how much of a difference would that make to someone with Fragile X syndrome?
HAMILTON: I asked Gurney that question exactly, and here's what he told me.
GURNEY: People with Fragile X with an IQ of 40 are typically living with their parents or in an institutional setting. With an IQ of 50, in some cases, they're able to ride the bus. They're able to hold a job with some assistance, and they're able to function better in their community.
KWONG: Oh, so that is a big difference.
HAMILTON: Yeah, it's significant. But what I found really interesting was something that Mark Bear told me. Remember, he's the guy at MIT. He said that if this or any drug really works for adults with Fragile X, it's likely to be much more effective when you give it to children.
BEAR: Fragile X can be conceptualized as a derailment of normal brain maturation. So the earlier we can get in there and correct the course of development, the more dramatic will be the improvement.
KWONG: It sounds, though, like adults such as Andy will probably get less benefit.
HAMILTON: Probably. But, you know, Katie Clapp told me that now, after more than 25 years of searching for a treatment for her son, she and her husband are really pretty thrilled at the prospect of anything that could help.
CLAPP: If this drug succeeds, then the sky is the limit for Andy, because then our job as parents would be to teach him - you know, drive down the road and say it's fall, and that's why the leaves are falling down, and here's why, and here's why, and show him his world.
KWONG: That's beautiful. I want that for them. So when do we find out whether this drug really does work?
HAMILTON: Probably pretty soon. That little company, Tetra Therapeutics - it's now part of a big Japanese drug company called Shionogi, and their plan is to start a large study this summer that would be the last step before seeking FDA approval.
KWONG: Well, Jon, I hope you'll come back when that study is done.
HAMILTON: I promise I will, Emily.
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KWONG: This episode was edited by Gisele Grayson, produced by Rebecca Ramirez and fact-checked by Rasha Aridi. The audio engineer was Josh Newell. I'm Emily Kwong.
HAMILTON: I'm Jon Hamilton. Thanks for listening to SHORT WAVE, the daily science podcast from NPR.
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