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A Boy With Muscular Dystrophy Was Headed For A Wheelchair. Then Gene Therapy Arrived

This is the story of a fatal genetic disease, a tenacious scientist and a family that never lost hope.

Conner Curran was 4 years old when he was diagnosed with Duchenne muscular dystrophy, a genetic disease that causes muscles to waste away.

Conner's mother, Jessica Curran, remembers some advice she got from the doctor who made that 2015 diagnosis: "Take your son home, love him, take him on trips while he's walking, give him a good life and enjoy him because there are really not many options right now."

Five years later, Conner is not just walking, but running faster than ever, thanks to an experimental gene therapy that took more than 30 years to develop.

Conner was the first child to receive the treatment — a single infusion designed to fix the genetic mutation that was gradually causing his muscles cells to die. The treatment can't bring back the cells he's lost (he remains smaller and weaker than his twin brother, Kyle), but it has allowed the muscle cells he still has to function better. Since Conner's treatment, eight other boys with Duchenne muscular dystrophy have received two different doses of the gene therapy. Preliminary results on six of them, tested a year after treatment, showed they, too, had improved strength and endurance at an age when boys with Duchenne usually become weaker.

The success suggests that gene therapy could be poised to change the lives of thousands of children — usually boys — who have Duchenne. But scientists still want to see the results of a much larger trial of the therapy, which is likely to begin later this year. Parents Christopher and Jessica Curran at home in Connecticut with their sons (from left) Kyle, Will and Conner. A race against time

Conner's parents, Jessica and Christopher Curran, never accepted the doctor's grim prognosis. But by the time their son got to first grade, he was falling far behind his fraternal twin, Kyle, and struggling to get around the house.

"He pulled himself up the stairs," Jessica says. "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?"

The Currans knew that scientists were working on a treatment. About a year after his diagnosis, they'd begun to hear the words "gene therapy."

It seemed like the answer. After all, children with Duchenne lack a functional version of the dystrophin gene, which helps muscles stay healthy. So why not fix it? Conner Curran explores his family's garden. The experimental treatment he got two years ago was an infusion of many copies of a harmless virus known as AAV that had been packed with some of the genetic code from a dystrophin gene. Once inside the body, these copies of AAV transport their payload of functional dystrophin code into muscle cells, where they replace a faulty version. "The concept is very simple. "You're missing a gene so you [put it] back," says Jude Samulski, a gene therapy pioneer and a professor of pharmacology at the University of North Carolina School of Medicine in Chapel Hill.

A molecular "FedEx truck"

Samulski devoted more than 30 years to make that simple concept work.

It all began in 1984 when he was still a graduate student at the University of Florida.

Samulski was part of the team that first cloned a virus that would become a staple of the gene therapy world.

It was an adeno-associated virus — part of the parvovirus family, which is best known for causing intestinal problems in puppies and skin rashes in children.

But AAV is remarkable because it infects people without making them sick or causing much of an immune response. So Samulski saw AAV as a potential way to safely transport healthy genes into ailing muscle cells.

"It's a molecular FedEx truck," he says. "It carries a genetic payload and it's delivering it to its target."

But delivering a gene is harder than delivering a package. And delivering the dystrophin gene proved especially challenging.

The approach Samulski had in mind involved packing some of the genetic code from a dystrophin gene inside AAV. Once the virus got into the body it would infect muscle cells and replace their faulty dystrophin code with a functional version.

One obstacle, though, was that AAV is tiny, even among viruses. Dystrophin, on the other hand, is the largest known human gene. It contains about 500 times the amount of genetic information found in AAV.

Another challenge was that Duchenne affects billions of muscle cells all over the body. So the AAV delivery truck would have to be programmed to reach, recognize and infect these muscle cells wherever they were found.

Over the next 15 years, progress came one small step at a time. Researchers led by Jude Samulski, a gene therapy pioneer and a professor of pharmacology at the University of North Carolina School of Medicine in Chapel Hill, developed the gene therapy that has successfully treated Conner Curran and at least eight other boys, so far.

The Muscular Dystrophy Association financed the effort.

"This was very challenging," Samulski says. "It was the Mount Everest of the gene therapy community and each one of these steps was like setting up base camp."

Gene therapy suffers a tragic loss

Then, in 1999, Samulski's base camp got hit by an avalanche. A teenager named Jesse Gelsinger died in a gene therapy experiment.

The experiment had nothing to do with muscular dystrophy or the AAV virus. But those details didn't matter.

"It stopped everything," Samulski says.

Gene therapy trials were postponed or abandoned. Investors disappeared. So did research funding.

But one group never wavered: the Muscular Dystrophy Association.

"If the MDA didn't step in, the field was going to dry up and die," Samulski says.

The MDA had helped fund the discovery of the dystrophin/DMD gene responsible for Duchenne, the most common and most serious form of muscular dystrophy. And the group was determined to turn that discovery into a cure.

So when Samulski approached the MDA about a grant, it made him an offer.

" 'Jude, we love the work,' " Samulski remembers hearing from the MDA. " 'We love the research. But we're tired of funding academics that just publish a paper. We need something to turn into a drug.' "

he MDA wanted Samulski to start a company to develop that drug, says Dr R. Rodney Howell, professor emeritus at the University of Miami and the association's board chairman at the time. The group knew that Samulski didn't have much business experience, Howell says. "But, on the other hand, he knew a tremendous lot about viruses and how they work and how they might really be effectively brought into the clinical practice."

So in 2001, Samulski and a small team created Asklepios BioPharmaceutical or AskBio.

"I remember Jude saying we probably won't get funding because gene therapy a is an unproven technology and there are a lot of naysayers," says Sheila Mikhail, AskBio's CEO. "But it has the potential to change the world."

Today, AskBio occupies a gleaming new headquarters in Research Triangle, N.C. It's part office building, part lab, and part pharmaceutical manufacturing facility.

During a tour of the building, Samulski pauses to point to a liquid-filled flask. "You see that media going around and around?" he says. "That's human cells that are growing." Then he shows me a device that uses sound waves to break open cells and expose the viruses inside.

The company didn't have this sort of tech early on. Even so, Samulski and his team managed to create an abridged version of the dystrophin gene — one small enough to fit inside their viral FedEx truck.

Then they started making deliveries — first in test tubes, then in mice, then in golden retrievers with a genetic mutation similar to the one Conner has.

Typically, these dogs "can't stand on their hind legs because they lose their quadriceps," Samulski explains. "And they usually don't get past 1 year of age."

But dogs who got the gene therapy did much better. And a video of those dogs eventually made its way to Conner Curran's parents.

"They were able to run and jump," Jessica says. "We saw this with our own eyes. And we just thought, 'Oh gosh, if one day Conner could get a chance to get something like this ...' — it just gave us so much hope." Playing with his brothers, Conner Curran (left) says the gene therapy has really helped him. "I can run faster. I stand better," Conner says. "And I can walk to Goldberg's — that's a bagel shop — and it's more than 2 miles and I couldn't do that before." Kholood Eid for NPR Samulski's company lacked the resources to bring its gene therapy to the thousands of boys with Duchenne. So in 2016, AskBio sold its treatment to the drug company Pfizer.

By early 2018, Pfizer was ready to start clinical trials of the experimental substance. And so was Conner Curran.

"He and his brave parents volunteered to be the first to get treated with the gene therapy," Samulski says.

As the day approached, though, Jessica had doubts.

"I looked at my husband and I said, 'Chris, are we doing the right thing for Conner?' " she says. "And he said, 'We need to be in this together Jess, and let's think about the alternative. And the alternative is death.' "

To Conner, the treatment with what he calls "muscle juice" was no big deal. "They put a needle in my arm for two hours," he says when I ask him what it was like.

What made a larger impression on Conner was his friendship with Samulski.

The scientist was with the family in the days after Conner was infused with billions of viruses. He was also there days later when Conner became feverish and stopped eating — a common reaction to this type of treatment.

When Conner was feeling better, Samulski had the family over to his house, where he played the piano for his young friend and showed him his garden.

"We talked about science, and viruses and snacks," Conner says. "I love him."

Conner Curran says getting the infusion of what he calls "muscle juice" was no big deal.

"They put a needle in my arm for two hours," he says. He and other boys getting the treatment did experience some side effects, though, ranging from fever and nausea to liver problems.

The treatment worked quickly. "Within three weeks he was running up the stairs," Jessica says.

"I can run faster. I stand better," Conner says. "And I can walk to Goldberg's — that's a bagel shop — and it's more than 2 miles and I couldn't do that before."

Conner's body will never replace the muscle cells he lost before his treatment. And though the approach has worked for more than two years now, it's not clear how long his new genes will last. It's also not clear whether Conner could safely get a second treatment.

But his improvement offers strong evidence that the approach can work. It's now been tested on nine boys. And Pfizer is planning a much larger study for later this year.

Meanwhile, other companies are also working on gene therapy for Duchenne.

Sarepta Therapeutics, for example, has received FDA approval for treatments aimed at two subsets of Duchenne patients and plans to use AAV to treat a broader group.

Still, scientists and doctors treating these patients agree that AAV therapy has flaws.

Several boys, including Conner, became ill temporarily after receiving the virus with symptoms ranging from fever and nausea to kidney and liver problems. Two ended up in the hospital. Pfizer is planning a much larger study for later this year of the same treatment Conner got, and other companies are now working on different types of gene therapy to treat Duchenne muscular dystrophy. So Samulski has been working on a fix.

The scientist stands at a whiteboard in a meeting room at AskBio. A half dozen researchers sit around a conference table littered with half-empty pizza boxes.

Samulski explains that every gene therapy trial using a version of AAV has run into problems with side effects, often affecting the liver. The problem seems to be a dangerous immune response prompted by the virus.

"We gotta solve this," Samulski says. "In my mind, this is the most important thing that we can do this year."

As usual, he has an idea.

"We want to build a stop sign in here," he says, pointing at one of the figures he's drawn on the board.

He tells the team to go create one.

When I speak to Samulski several months later, he tells me that the team has delivered the stop sign he requested. The lab is now doing tests in animals to see whether it works.

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