When Rebekah and Evan Lockard’s daughter, Naomi, was diagnosed with a devastating ultra-rare genetic disease, they didn’t know where to turn. Then they found Terry Pirovolakis, an IT professional who had made a gene therapy for his son with the same disease. But the process of getting Naomi treated has been an uphill battle, full of financial and logistical obstacles. The Lockard’s story flips the question we’ve been asking all season on its head. Instead of wondering, “if we could do something, should we,” we’re now asking, “if we can do something that helps patients, should we do it at any cost?” And this question isn’t for scientists or researchers, it’s for the rest of us.
Credits
Host: Alexis Pedrick
Executive Producer: Mariel Carr
Producer: Rigoberto Hernandez
Associate Producer: Sarah Kaplan
Audio Engineer: Samia Bouzid
Music by Blue Dot Sessions
Resource List
Mast, Jason. “A dad built a gene therapy for his son. Can he save other kids, too?” STAT News.
“Battling SPG50 and changing the world.” August 17, 2022. The Jackson Laboratory.
Brent, Jonathan R. and Deng, Han-Xiang. “Paving a way to treat spastic paraplegia 50.”
“AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.” June 28, 2004.
“Colorado family pushes for more funding, awareness around rare neurological disorder.” August 12, 2024. CBS News Colorado.
Transcript
Alexis Pedrick: From the Science History Institute, I’m Alexis Pedrick and this is Distillations.
Last episode, we talked about the major problems gene therapy faced in its first three decades. In this episode, we’re going to talk about the problems it faces today, especially when it comes to rare genetic diseases.
And to do that, I want to introduce you to Naomi Lockard, a four-year-old from Colorado. This is her mother, Rebekah Lockard.
Rebekah Lockard: Naomi loves Miss Rachel, so she makes us sing all day long. She is a very picky eater these days but loves kind-of her “snacky” foods. And she’s been really into, like, Mega Bloks recently. And she really loves to play with them with us, which is fun.
Alexis Pedrick: When Naomi was born in 2021, she seemed perfectly healthy. In fact, her parents, Rebekah and Evan, felt like they’d won some kind of baby lottery; she was so calm and easy.
But then she started seeming a little too calm. She barely cried. And then the baby milestones came and went, and dread set in.
Rebekah Lockard: She started falling off her growth curves, and she struggled a lot with breastfeeding. But our pediatricians kind of wrote us off in the beginning and said she’s, you know—we’re just, you know, first-time parents who were really worried.
Alexis Pedrick: And this is her father, Evan.
Evan Lockard: “Milestones are just guidelines. Don’t worry about it.”
Rebekah Lockard: “Yeah, she’ll catch up.” But at six months, it was starting to become clear.
Like, she’s not–she’s not doing what she needs to do. She’s not rolling over. She’s not doing much of anything. She was really behind cognitively, and her communication was behind.
Alexis Pedrick: After doing an early intervention intake, Naomi started getting physical therapy and play-skills therapy each week. After a while, her therapist became concerned.
Rebekah Lockard: They told us that something was up, that it wasn’t making sense to them, that she wasn’t starting to catch up with these interventions that are proven to work. And so they recommended just a slew of testing for her.
Alexis Pedrick: Blood, hearing, eyesight, cardiology, and MRI. Everything came back normal. After exhausting all options, doctors recommended genetic testing.
Rebekah Lockard: They were recommending us: “just do, you know, testing.”
Evan Lockard: Targeted for, like, muscular-
Rebekah Lockard: Muscular conditions-
Evan Lockard: Issues, you know, because she’s so far behind gross motor skills.
Alexis Pedrick: Instead, they decided to do something called “whole exome sequencing.” The exome is the part of our DNA that codes for proteins. It’s only 2% of the genome, but an estimated 85% of disease-causing genetic mutations reside in it.
It was expensive: $3,000. But Rebekah was pregnant with her second child, and she’d already reached her deductible. So they went ahead with it. They had no idea this expense was just the beginning.
Rebekah Lockard: We swabbed Naomi, her cheeks, for saliva. And then we did the same, so they could, you know, compare her test to see if there was something hereditary and send it off. And it took, I mean, literally like, three plus months to come back.
Alexis Pedrick: And it was a good thing they did it because, in May of 2023, it’s how they found their answer.
Rebekah Lockard: We got the genetic test results dropped into MyChart, and it said she was positive for this condition. And, you know, it kind of walked through like a lot.
I just remember a lot of words that I did not know what they meant, but a lot of medical words. But there was things like “paraplegia” and “severe cognitive impairment.” And I think we kind of started to realize, like, this is bad.
Evan Lockard: It was, I was at work and Bekah called me and said, “I don’t know what any of this means, but I think it’s bad, and I think you should come home.”
And then we were on the phone with our neurologist, like, 45 minutes later.
Alexis Pedrick: Naomi was diagnosed with hereditary spastic paraplegia 50, or SPG 50.
Rebekah Lockard: I remember calling the neurologist crying and was like, “We need to, you know, talk to somebody like now.” And I read later in the note, like, “Mother is teary, like, needs contact ASAP.”
And you know, it was—our neurologist is great. We have a good relationship with them, but they didn’t know what the condition was.
Evan Lockard: They were learning about it like on the call as we were talking to them. So it was, yeah, it’s hard to, I mean, those are the people you go to for answers. And it’s hard when they don’t have any answers.
You know, you just don’t know. What do you do?
Alexis Pedrick: SPG 50 is an ultra-rare genetic disease. Fewer than 100 people on the planet are known to have it. It affects the central nervous system, the brain, and the spinal cord and causes an array of symptoms.
Rebekah Lockard: At first, for kids, it causes a developmental delay. They just progress really slowly in all areas. And then in early childhood, around elementary school age, they start to lose whatever skills they’ve developed.
And so it comes with progressive paraplegia. The kids are generally non-verbal, and they have a moderate to severe cognitive impairment. So, it really affects all areas of life.
Alexis Pedrick: Most people with SPG 50 become paralyzed by age ten and quadriplegic later in their lives. Many never learn to talk or walk, and it’s all because of one gene.
Evan Lockard: It’s a mutation in the AP-4 gene.
Rebekah Lockard: And it was clear that she had that mutation. And then they had what our mutations were: the inherited genes. So, Naomi had received one bad copy of this gene from me and one from Evan.
And then there was a 25% chance that any other kids we had would be affected as well, which was devastating because we were four weeks away from Jack being born.
And so we were just shocked. Like, you know, not only do we have one very high-special needs kid, kind of all of a sudden the next baby, who’s about to be born, might also have the same.
Alexis Pedrick: Ultra-rare genetic diseases have so few patients that there’s rarely a charted treatment course. In fact, there’s rarely drugs on the market. But one thing a genetic disease does have is a very clear cause. And often it comes down to one problematic gene, and that’s where gene therapy comes in.
It’s a simple idea, really. You can give someone with a genetic mutation a corrective gene. In practice, it’s much more complicated. But for families with rare genetic diseases like the Lockards, it’s their only hope.
Their story begs the question that flips the one we’ve been asking about scientific breakthroughs all season on its head. The question has been, “If we can do something, does that mean we should?” But now the question is, “If we can do something that helps patients, should we do it at any cost?” And this question isn’t for scientists or researchers; it’s for the rest of us.
Chapter One. Bootstrapping the Way to a Treatment.
Alexis Pedrick: As soon as Rebekah and Evan got off the phone with their neurologists, they did what anyone would do. They went to Google, and while they didn’t find much information on SPG 50, they found something better, or rather someone better.
Terry Pirovolakis: My name is Terry Pirovolakis, and on April 2nd of 2019, my youngest son, Michael, was diagnosed with spastic paraplegia type 50.
Alexis Pedrick: Terry’s son had been diagnosed with the same thing as Naomi a few years earlier. He and his wife, Georgia, were told they couldn’t do anything for their son. They should just go home and love him.
Terry Pirovolakis: “He’ll be paralyzed from the waist down by the age of ten, quadriplegic by the age of 20. He’ll never walk. He’ll never talk. And we don’t know how long he’ll live for.”
Alexis Pedrick: Doctors told them that there was no cure for SPG 50. There was no clinical trial to join, no treatment to sign up for. There were no options.
Terry Pirovolakis: My wife and I went home that night. We just died. And we realized that the next day, or that night, that we had to do something and that we were willing to do everything in our power to change the course of his disease.
Alexis Pedrick: Terry decided to forge a path where none existed, but he did have a bit of a roadmap in his career as an IT professional for large banks.
Terry Pirovolakis: So going back, if you went back to my career before Michael was diagnosed, I spent, you know, 20 years in IT, building large infrastructure around the world. And we just really pushed the boundaries around what we were doing at the time: very large projects that most people thought could not be done.
So when Michael was diagnosed, I thought to myself, “Well, if I can do this all for companies, why couldn’t I do this for my child? Why couldn’t I figure out a path forward?”
Alexis Pedrick: Just like the Lockards, Terry went online, and he found that families with a similar disease, SPG 47, had been bootstrapping their way to a gene therapy treatment.
Terry Pirovolakis: We knew that gene therapy was what we wanted to do. We just needed two things. We needed the right team, and we needed money.
Alexis Pedrick: The Pirovolakises are not wealthy. Terry is neither a doctor nor a scientist, but he wouldn’t stop until he got gene therapy for his son. Within four days, he had refinanced his house.
Terry Pirovolakis: We filed for a charity. We liquidated our life savings. You know, three days later, we had contacted Jackson Laboratory in Maine, begging them to make a mouse model for my son.
Alexis Pedrick: He flew to the American Society for Cell and Gene Therapy Conference in Boston, carrying a poster that said, “Wanted a Cure for Michael. Reward Research Grant.”
Terry Pirovolakis: During that conference, I interviewed the FDA, the NIH, people from the NIH, companies, scientists, researchers. And I asked them all the same question: “If he was your child, what therapy would you do?” And 90% of them said, “gene therapy.”
And then the second question was, “Who would you hire to make you the gene therapy?” And almost everybody said Dr. Steven Gray. When I started researching it, I realized that there was about 4 or 5 world experts in gene therapy for the brain specifically.
Alexis Pedrick: And Steven Gray was one of them. And he was there at the conference receiving an award.
Terry Pirovolakis: So right after he won the award for top geneticist—or whatever that award was for—I ambushed him on the stage. And he was telling me that he already had 30 programs, that he was very busy and that he just, he didn’t want to take my program on and not give it the attention it needed.
And I said, “I’m not taking ‘no.’ You’re going to have to figure it out. And we’re going to work together. We’re going to, we’re going to save Michael.”
And that was kind of the beginning of our relationship.
Alexis Pedrick: Something to know about Terry is that he is six foot three and burly: a gentle giant with a bushy beard and kind, crinkly eyes. And he is very, very persuasive. Steven Gray couldn’t say no.
Terry Pirovolakis: I’m persistent, and I think people see that I’m serious and that I don’t mess around. And what I say, in my word, matters. And I do things that I promise to do.
So, when I tell people that I’m going to raise $4 million, they know I’m going to do it. If I say I’m going to get, you know, paid something down or make a commitment, my word is my bond, and I’m going to do it. And I don’t care what it takes.
Alexis Pedrick: Steven explained that the road ahead would be very difficult, very expensive, and that there were no guarantees. Terry didn’t flinch.
Terry Pirovolakis: I flew around the world. I met experts in gene therapy.
Alexis Pedrick: He organized galas and golf tournaments. He sold doughnuts outside of concerts.
Terry Pirovolakis: I rode my bike from Toronto to Ottawa, which I’m not physically fit. And I met the prime minister of Canada, and we’ve done hundreds of events.
Alexis Pedrick: And he told his story to anyone who would listen, just trying to get support.
Terry Pirovolakis: And over the course of three years, we raised $4.5 million.
Alexis Pedrick: Finally, they were able to make the gene therapy in Dallas, Texas.
Terry Pirovolakis: We got a safety test in Quebec. We had the FDA and Health Canada approve it. And the reason why we were able to do it so fast is because we had the money to do things quickly.
So, for example, while we were proving that it worked, we started toxicology studies. While we were doing toxicology studies, we were doing manufacturing. So where you would normally do everything in sequence and take 5 to 7 years, we were doing everything in parallel.
Alexis Pedrick: And finally, in March of 2022, Michael got gene therapy at the University of Texas. It was a clinical trial of one.
Terry Pirovolakis: About a month afterwards, he went from standing on his tippy toes to being flat-footed. We noticed more so his cognition. You know, he started hugging, kissing my wife. He started playing with his toys with intent. He’s able to communicate more nonverbally but with his device. And we kind of understand what he wants.
So there was a lot of things that improved mentally. Physically, we’re just hoping that we slow down or stop the disease. And for that, we won’t know for a couple of more years.
Alexis Pedrick: Afterwards, Terry’s thoughts immediately went to other kids out there with SPG 50. He figured he had this proof that the treatment was safe and it worked, and he could then hand it off to a drug company with the resources to do more trials and bring it to market because obviously this was not a sustainable model. But it was not as straightforward as he thought it would be.
Chapter Two. Moving Heaven and Earth.
Alexis Pedrick: When Rebekah and Evan googled SPG 50 in May of 2023, Terry’s website “CureSPG50.org” immediately popped up.
Rebekah Lockard: You know, filled out like the “Contact Us” on his website. And he pretty much immediately was texting me and offering to be there if I needed support.
He knew how horrible the diagnosis was, and we ended up talking to him, doing a Zoom or a FaceTime the next day, or the day after: Saturday or Sunday.
Alexis Pedrick: Finding Terry was like discovering a candle in the darkness. Here was someone in their exact position who had paved a path before them.
Evan Lockard: It’s like the sky falls down, and then all of a sudden, you know, you got an umbrella. So it was, I mean, it was a lifeline for me especially.
I mean, I kind of just shut down. Rebekah keeps saying we did all this research, but it was all Bekah. She- all of it was Bekah. She’s awesome.
Alexis Pedrick: They asked Terry about getting Naomi treated just like Michael had been.
Rebekah Lockard: “Is it possible for Naomi to to do this? Is it something that you know that we can hope for?”
Alexis Pedrick: Terry promised them that he would do whatever he could for both children if necessary.
Rebekah Lockard: He said, you know, “Of course, like, I hope and pray that your baby’s not affected. But if he is, we’ll figure that out, too.”
Alexis Pedrick: Jack was born four weeks later, and this time the genetic testing was much quicker because they knew exactly what to look for. Still, they had to wait five weeks, and in that time, they agonized over whether or not he seemed to have SPG 50.
Evan Lockard: I was convinced that he didn’t have it just because how… just farther along he seemed to Naomi at the same point. I mean, he just seemed so much stronger, so much more physical: just everything. I was convinced. I don’t know; I guess I shouldn’t have put it out there.
Alexis Pedrick: But then they realized he wasn’t getting enough breast milk when he was nursing.
Rebekah Lockard: So, he was falling off his growth chart. He was losing weight kind of rapidly. And we started introducing bottles. And the first kind of night we gave him a bottle, he aspirated the formula, and we took him into the hospital because he was having retractions in his chest.
He was, you know, kind of looked like he was struggling to breathe. And we’re sitting in the hospital. He’s on oxygen. You know, it’s middle of the night. And then his genetic test drops into MyChart.
And I don’t know, I remember reading it, and I couldn’t even. I couldn’t grasp, like, what it was saying, even though I read Naomi’s kind of accurately and right away. And Evan was the one who was like, “Well, it says positive at the top. So he has it too.”
And I just remember sobbing in the hospital. And, you know, doctors and nurses are coming in to deal with this very typical, like, aspiration case. And, you know, telling me like, “It’s okay. This is- I know it’s hard to see your baby in the hospital.” I’m like, “I don’t care.”
Evan Lockard: So much other stuff is going on.
Rebekah Lockard: I don’t care that he’s in this little, like, cage-like crib, hooked up to oxygen. That’s the least of my worries.
Like, “I know you’re just trying to be supportive. But, like, you know, you don’t realize, like, our whole world just fell apart again.”
Evan Lockard: Read the room.
Rebekah Lockard: You texted Terry. “Okay. The baby’s positive.” And I remember he called me immediately.
Terry Pirovolakis: And I said, “I’m so sorry. You know, my heart goes out to your family.”
Rebekah Lockard: He was like, “We’re gonna treat your baby. Like, don’t worry. We’re gonna treat him.”
Alexis Pedrick: But Naomi would have to wait. And here’s why: after Michael got treated in the phase one trial, the team found themselves with extra doses of gene therapy. And they treated a few other children.
Terry Pirovolakis: So what happened was we ran out of drug product after the first three children were treated. And we were lucky that the manufacturer was kind enough to make us another batch.
That batch was only enough to treat a certain amount of children that are older than two, and a certain amount of children under two. We didn’t have enough drug products to treat Naomi because we didn’t have enough drug product for over two years of age.
Rebekah Lockard: They had extra doses, but they were only baby-sized. So, she needs a full dose. But a baby, because their brain is smaller, could take a baby-sized dose.
And so they were working on, I think, getting more medicine produced. And also they wanted to run this phase three trial.
Alexis Pedrick: Because the ultimate goal, remember, was to get the drug to market so people could buy it with insurance. But it wasn’t clear when that was going to happen. In the meantime, they could treat Jack, and there was an imperative to do it as quickly as possible.
Rebekah Lockard: I mean, it’s a condition that affects brain development. And the brain rapidly develops in the first two years of life. Like, there was a lot of incentive to get it done quickly.
Alexis Pedrick: But at the time, the minimum age for the trial was one-year-old.
Rebekah Lockard: And so they did all this work to, you know, make sure it was safe and to get the FDA on board and to get the hospital ready. And they were working in the background: Terry and his team.
Evan Lockard: They moved mountains. They had to go back and forth with the FDA to change the trial protocols, and they got meetings with experts about, like, “How young can a person receive gene therapy?” And yeah.
Rebekah Lockard: They were, I mean- truly moved heaven and earth to make sure he could be treated as soon as possible.
Alexis Pedrick: One day before Jack was five months old, Rebekah and Evan got the word. Everything was ready. They had to be in Dallas in two weeks, and they’d need to be there for two months: one month of tracking Jack, one day of administering the gene therapy, and then a month of follow up.
And they had to make a really painful decision about Naomi.
Rebekah Lockard: She couldn’t come with us.
Alexis Pedrick: Part of this decision was so Naomi could keep getting the therapy she needed. But the other piece was because of the viral vector the gene therapy used. The way gene therapy gets corrective genes into the body is with a virus.
Jason Mast: Viruses are tiny little machines that have been evolved over eons to hack into human, animal, other types of cells.
Alexis Pedrick: This is Jason Mast, a reporter for STAT Newswho wrote an article about Terry Pirovolakis and the Lockards.
Jason Mast: And so they are basically built by evolution for this exact task that gene therapy researchers are trying to solve, which is “how do we break into human cells and put something there?”
And so if you hopefully find the right viruses, tweak it in the right way, it can shuttle that to the right part of the body.
Alexis Pedrick: Terry’s gene therapy uses an AAV9 vector. It’s safer than the viral vectors we talked about in the last episode, but it’s still technically contagious.
This means that gene therapy is a one-time thing. You can only be exposed to the virus once. Which brings us back to Jack and Naomi.
Rebekah Lockard: And so if Naomi was around Jack while he was shedding, she could catch the virus, develop antibodies, and then she would be precluded from treatment because she would already have had an immune response to the virus and would likely just kick it out of her body.
So, to preserve her chances for treatment, we left her in Colorado, and that was horrible.
Alexis Pedrick: Jack was treated in December of 2023, just a few days shy of his six-month birthday.
At the time, he was the youngest child in the world to have ever received any type of intrathecal gene therapy. This means it was injected into his spinal fluid with the hopes of it reaching his brain.
Evan Lockard: Handled it like a champ. They had all kinds of precautions in place. Some of the kids that were treated got kind of sick, like, you know, your body’s reacting to this almost like a flu reaction where you’re vomiting and all this stuff.
And Jack, I mean, he woke up from anesthesia and was just, like, the happiest little man. And he ate great. And, you know, he was just rolling around, couldn’t understand why he was confined to this cage.
Alexis Pedrick: The procedure itself took just two hours.
Rebekah Lockard: I remember feeling a lot of relief, like, “It’s happening. It’s done. Like we are doing- this is ,like, the only thing we can do for Jack. You know, we might have a long road ahead of us for therapy and medical appointments, but like, we’ve gotten him the treatment he needs, and we can rest easy knowing that we saved him.”
Alexis Pedrick: As soon as Jack woke up from his procedure, Rebekah and Evan saw changes.
Rebekah Lockard: You know, before treatment, he just- I don’t know. I never felt like he really connected with, at least, me. I just felt like he kind of looked through me, and he wasn’t as social as Naomi was.
But after Jack got the treatment, I remember he, like, looked at me and was actually like looking at us and not through us, and that was really incredible to feel.
Evan Lockard: Really great feeling. It was like when he woke up. Yeah. He looked at us, and it just- Like, there was just a connection there that wasn’t there before. It was amazing.
Rebekah Lockard: I felt like he looked at me and was like, “Oh, that’s my mom.” Like, “I know her.”
Evan Lockard: “I recognize these people.”
Alexis Pedrick: Jack is now two.
Rebekah Lockard: And he’s doing awesome. You know, he’s moving around a ton. He’s very curious about things. And we just see a lot of progress with him. He’s behind his peers, but he is caught up to Naomi in most developmental areas, and that tells us it’s working.
I mean, even if he has delays the rest of his life, if he has any semblance of a normal life or, you know, avoids the paralysis, I mean, that’s a win, right? It’s a no-brainer.
Chapter Three. The Money Problem.
Alexis Pedrick: If things had gone the way Terry had hoped, a biotech company would want to license his gene therapy and take over, but no one wanted it.
This is Jason Mast again. His story covers how hard it is to get companies interested in gene therapies for rare diseases.
Jason Mast: It comes down to basically two things. There’s how expensive it is to make a drug and how few patients there are. I mean, Terry had an ally in pharma who works at a rare disease company that specializes in rare disease. And he was like, “I can’t convince my board to take this on because it is just too rare.”
So, you lose this profit motive that is so built into our system of how we make drugs. And drug development is really expensive, and making these viruses is really expensive. And doing this animal testing is really expensive.
Alexis Pedrick: Even though a disease might be conceptually simple—like one mutated gene in the case of SPG 50—and even though a possible therapy can be sketched out in just hours, the costs beyond that are astronomical.
Engineering, manufacturing, testing can cost tens of millions of dollars, and there’s no way to recoup these costs when there are so few patients with the disease.
Jason Mast: At the end of the day, there’s only 500 patients. There’s only 60 patients. There’s only 1000 patients. Not the, you know, million patients with diabetes or millions of patients with diabetes that we want that we can make millions or billions of dollars off of. And so we’re going to go put our resources elsewhere.
Alexis Pedrick: This is Matthew Cobb, a zoologist and the author of As Gods: A Moral History of the Genetic Age.
Matthew Cobb: So, you’ve got not a great deal of interest from the pharmaceutical industry. And the patients end up organizing to crowdfund, as we now say, because neither governments, nor health institutions, nor insurance companies, nor pharmaceutical companies are going to pay for this.
Alexis Pedrick: When no one came to license the gene therapy, Terry made another unusual and, frankly, slightly crazy move. He started his own biotech company. Remember: not a doctor, not a scientist.
Terry Pirovolakis: I then quit my job after realizing that no one wanted to take this program on to save more children and create a company called “Elpida Therapeutics.” It’s run like a nonprofit, but it is a formal company in California. And now we’re here trying to save more kids.
Alexis Pedrick: Terry admits the business model is crazy, but he sees no other option.
Chapter Four. The Effectiveness Problem.
Alexis Pedrick: Unfortunately, money is not the only problem with gene therapy. There’s also an effectiveness problem, which in turn makes the money problem worse.
No one is claiming that the gene therapy for SPG 50 is a cure. And the older the patient is when they get it, the effectiveness decreases. This is Jason Mast again.
Jason Mast: You want to be able to treat someone while they still have the maximal number of neurons and while they’re still developing, so they can form whatever connections or, you know, experience as close to a healthy development as possible.
Alexis Pedrick: Jack’s situation is even more rare than most rare disease cases because of the head start he had. His parents knew to test him as soon as he was born, and they knew exactly what to test him for because of Naomi. Naomi was almost two when she was finally diagnosed. Jack was just five weeks old. In order to get the maximum benefits of gene therapy for a brain condition, that’s how young you need to be diagnosed. But it rarely happens.
Jason Mast: People don’t get sequencing when they’re born, and they don’t get sequencing often when they first show up to a doctor. And so, it can often be a sort of a journey, as it was for both the Lockhards and for Terry and Michael, to get this kind of testing that they need. And that imposes all kinds of delays and actually ends up making trials harder because you’re helping patients later on, so you don’t see as strong benefits.
Alexis Pedrick: Rebekah and Evan are hopeful that Jack will get more benefits than older patients, but there are no guarantees. As we’ve covered on this show before, the brain is a notoriously difficult thing to treat.
Jason Mast: The key thing is that, like, there is this blood brain barrier. And it’s there to keep bad shit out of your brain or bad stuff out of your brain–however, your explicit rules are on this podcast. And so that becomes a huge challenge for “how do you engineer stuff to get out of this?”
You know, we talked about picking viruses because they’re evolved over eons to hack into human cells. And here you have this blood brain barrier that has evolved precisely to keep stuff out of the brain. And so you have this, like, unstoppable force, immovable object kind of type thing. And we are working on it, but yeah, it becomes very difficult.
Alexis Pedrick: The most effective gene therapies out there treat the blood and the liver. It’s simply easier to deliver gene therapy to those organs. The blood can be treated outside of the body and then put back in. And the liver is basically a big sponge.
Terry Pirovolakis: The virus that we’re using—when you inject it into the brain—we’re getting maybe 5 to 10, maybe 15% of the cells being transduced with the gene that’s missing. It’s not a good vector.
Alexis Pedrick: Meanwhile, the financial ask is huge, and there is no financial market reward like there might be for a disease with more patients. In short, the calculus is something like this: you can have a mediocre treatment if you have enough patients that would benefit from it. But if you only have a small pool of patients, investors expect a home run.
Terry Pirovolakis: The expectations from venture capital is that you’re going to make this, and every drug is going to be perfect. You’re going to snap your fingers, and you’re going to go, like, 0 to 100.
Alexis Pedrick: And even when a drug is perfect, money is still hard to come by. A good example is something that happened in the mid-2010s. Back then, there were exciting gene therapy results for a few diseases, including spinal muscular atrophy: a condition that will often kill infants before they reach the age of two.
Jason Mast: And this gene therapy comes along. And if you get it in time, like, kids grow up and live fully healthy lives. Or, at least, you know, so far; we’re only so many years out.
But the results look amazing. There are kids running around. It’s incredible. And there was also excitement. All this money coming in. They thought they were going to go after all these other conditions. And that will begin to crumble in a few different ways.
Alexis Pedrick: At first, people thought gene therapy could be turned into more of a modular technology, so you wouldn’t have to start from scratch and reinvent the wheel for each new therapy.
Jason Mast: Almost like a DVD player or a cassette player or something, where you just sort of slot in the gene that you want into this virus, and you send it into the patient. And it doesn’t matter what disease they have. Within certain limits, you can just swap in whatever gene, and you’ll have some success. And it’s not going to be all that costly.
And they find out that it’s a lot more complicated, and it’s a lot more costly.
Alexis Pedrick: So costly, in fact, that some seemingly curative therapies have been abandoned, including one for severe combined immunodeficiency disorder, or SCID.
Jason Mast: And there is where you really see this market failure in full relief. They published data in the New England Journal of Medicine showing how amazing this therapy was. And it was, like, basically, like, two weeks after—or two weeks before—they shelved the program. You know, it’s too rare.
Alexis Pedrick: Meanwhile, Terry’s gene therapy has two strikes against it: a tiny patient population and results that are not curative.
Terry Pirovolakis: But it’s the best thing we have now. And it’s something to give our kids a better life. And we have to run with it. And then when something better comes along, it’ll take over what we have.
Alexis Pedrick: Some hopeful news is that there are better viruses on the horizon.
Jason Mast: Folks are working on making newer and better viruses. There’s been a lot of really amazing lab data, but it’s still mostly just lab data. Human trials starting up, actually, as we speak. But it’s still, you know, in process.
Alexis Pedrick: And the kids who have SPG 50 now don’t have time to wait for newer, better viruses. They can’t afford to let the perfect get in the way of the good.
Terry Pirovolakis: I think everybody’s waiting for the next therapy to come around: some magic to come up. And what’s happening is the field is basically saying, “Well, forget what was built before. Go with the new stuff.”
Well, I heard that five years ago when I started. I heard the same thing. “Forget AAV9, and let’s go to the new thing.” But if we keep waiting, we’re never going to get there. And if you look throughout history, every drug product that has come around—monoclonal antibodies and vaccines—they’ve all had an incremental process to get there. We just have to do the same thing with gene therapy. It has to be incremental.
Alexis Pedrick: It brings us back to that big question: if we can do something that helps patients, should we do it at any cost?
This is Matthew Cobb, the zoologist and author we heard from earlier.
Matthew Cobb: This is a terrible, terrible problem. You know, meanwhile, there are, you know, millions of people who don’t have clean water. So, you know, this problem of very precise cures for individuals with very rare diseases can be set against—but probably shouldn’t be set against—the picture of broader public health.
You know, that’s the starting point of challenging that and saying, “Look. There is room for everything, but that we need a different approach to healthcare both in the US and in other countries and to funding it.”
And that’s a much bigger issue. And that doesn’t help the parents who are caught in the dilemma you’ve just described.
Terry Pirovolakis: It’s hard because people see it as, you know- We had one donor that was going to help us out. And then what happened? They realized that they can get their name on a building for $10 million, on a hospital. Right? Or they can feed 100,000 kids in New York for two years. You know, like children that need food.
And the dilemma is, there’s so much need in the world, right? And getting in front of someone that has immense wealth or immense connections or influence is hard because someone needs to introduce you to that person. You just can’t cold call them or get ahold of them. It’s very difficult.
Alexis Pedrick: And then there’s this: does the answer to the first question change if the cure is not a cure at all, but merely an improvement? Albeit a life-changing one?
Jason Mast: How do you make the case and find the resources and convince the regulators and all the right people to scale this when it’s not curative? When you think this can have a benefit, but it’s not, you know, the “end all, be all” of what medicine will hopefully be able to do. You know, maybe it can’t cure, but it can at least give your kid a chance at having a level of benefit, and you should have a right to try that.
Chapter Five. Naomi’s Wait.
Alexis Pedrick: As of the airing of this episode, Naomi is four years old plus two months. Every day that goes by without her getting treated feels like a wasted day.
Evan Lockard: It’s horrible.
Rebekah Lockard: Horrible! You know? I just, I think every day, like, “What kind of mom doesn’t get both of her kids treated? Like, you only got one treated…” Like, you know? We know that if Naomi gets treated, it will not be a cure. Everybody has been really clear on that.
But what would it mean if she could walk up the stairs instead of needing an elevator? Right? You know, what does it mean to, like, be able to use your hands or to move your legs? I mean, you know, I think we’ve all kind of operated under the assumption that, like, once paralysis sets in, it’s not going to be reversed. Maybe it can be stopped but not reversed.
And so, we’re hoping that Naomi gets treated before that sets in. And her feet are starting to turn in, starting to look like clubfeet. And it’s slowly progressing. And they’re still movable, which is what we want. But she’s starting to have the effects of it set in. So, she’s working really hard to gain skills and to learn to walk and to do all of this amazing stuff.
If we don’t treat her, she’s going to lose it. She’s gonna lose the ability to move her feet and then lose the ability to move her legs and then her torso and her hands and everything. It’ll just be- She’ll be a vegetable. And it’s just not. It’s not fair when you know that it’s preventable. And the only thing standing in the way is money.
Alexis Pedrick: Terry had hopes to move into a phase three trial, but grant money fell through.
Terry Pirovolakis: The new Trump administration came in, and I’m Canadian, so there’s no politics here. And they defunded the NIH. They stopped most of the grants, and they took overheads away from universities and hospitals.
For almost six months to a year now, we’ve had drug products sitting in the freezer. And it’s a shame because it’s just sitting there. We can treat these kids. We just don’t have enough money to, one, pay back the drug product that was supposed to be paid by the grant, and then, two, to pay the hospital to treat these children because it costs us almost $3 million to make eight doses. And then it’s going to cost us another quarter million per patient to treat them at the hospital.
And we had hoped that we would get a grant or funding or VC funding to do this. But because everything fell apart in the last three months: government grants; PRV went away; overheads are gone, right? There’s just no mechanism to treat these kids anymore.
Rebekah Lockard: Like it’s not. It’s not even 500 grand. It’s millions of dollars that is needed. And so it’s hard because we don’t have that kind of money. We don’t know anybody that has anywhere near that kind of money to give. And again, the economy is- It’s tough. I mean, you know, people can’t afford to buy eggs, like, who’s going to give to some condition that they’ve never heard of and that doesn’t impact them. So, it’s really hard.
Evan Lockard: It’s just kind of perpetually bad news. Yeah. You know, like, “Oh, she’s got this diagnosis. Oh, we can’t treat her. Oh, this is getting pushed out. This is getting pushed out.” Every time something like a glimmer comes through, you know, I get my hopes up, and then they just get dashed quick.
Rebekah Lockard: Naomi and Jack are- They’re wonderful kids. They’re really- We’re lucky in a lot of ways. They’re so happy. They play well together. They love each other. They give us kisses, and they have their own unique interests. And so, we are lucky to have them as parents. We don’t wish for this. They’re kids. They deserve a full life.
It’s not Naomi’s fault that Evan and I have this gene that’s messed up that we didn’t even know about, because it doesn’t affect us, right? And it can be fixed. But I just think we should do everything for kids to give them good lives. And, you know, the fact that it’s- This is within reach but can’t get it. It’s really hard.
Alexis Pedrick: You can look at this story and Terry, in particular, in two ways. On the one hand, he’s a superhero. He saw an unsolvable problem and solved it. And in the wake of it, he’s become a beacon of light for others. But on the other hand, maybe we should also be asking why an IT professional from Toronto has to become the first stop and last hope for families with this ultra-rare genetic disease.
Jason Mast: Writing about him reminded me a bit about- and these have kind of become, I think, memes to a certain extent online: where you see, like, ABC News celebrates a kid who’s like selling lemonade to raise money for their cancer treatment, or for someone else, or for someone else’s cancer treatment. And that’s supposed to be like a feel-good story of, like, a kid doing this, like, great thing and, like, entrepreneurship.
And it’s like, no, that’s a terrible fricking story. That’s like a searing indictment of our healthcare system that, like, a kid has to be raising money for either them or someone else to, like, actually get treatment. That is not how you build a healthcare system. We should not be relying on GoFundMe to supply treatment to people who are in desperate need. That’s not just. It’s not ethical. It’s not scalable, and it’s not going to actually fix this problem.
Alexis Pedrick: Gene therapy has emerged from its dark ages. It still has a long way to go. There are still debates about effectiveness and safety, but this story is a reminder that sometimes the biggest problems science faces aren’t in the lab.
Distillations podcast is produced by the Science History Institute and recorded in the Laurie J. Landau Digital Production Studios.
Our executive producer is Mariel Carr. Our producer is Rigoberto Hernandez. Our associate producer is Sarah Kaplan, and our sound designer is Samia Bouzid. This episode was reported and produced by Mariel Carr.
Support for Distillations has been provided by the Middleton Foundation and the Wyncote Foundation. You can find all of our podcasts, as well as our videos and articles, on our website at sciencehistory.org. And you can follow us on social media @scihistoryorg for news about our podcast and everything else going on in our free museum and library.
For Distillations, I’m Alexis Pedrick. Thanks for listening.
