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

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Conner Curran, 9 (right), and his brother Will, 7, at their home in Ridgefield, Conn., this week. The gene therapy treatment that stopped the muscle wasting of Conner’s muscular dystrophy two years ago took more than 30 years of research to develop.

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Since Conner’s treatment, eight other boys with Duchenne 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.

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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 1st grade, he was falling far behind his fraternal twin, Kyle, and struggling to get around the house.

The Obvious Question

«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 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.

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«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 making 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.

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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.

AskBio

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AskBio

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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 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.»

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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.»

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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.

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The Curran family (from left): Kyle, 9, Jessica, Conner, 9, Chris and Will, 7, with their dog Hunter, a miniature schnauzer. 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.

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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.

• muscle health
• muscular dystrophy
• biotechnology
• gene therapy