January 26, 2010 in Features

What they lacked in Hollywood looks, Duke researchers made up for in substance

Sarah Avery I Charlotte Observer
 
movieweb.com photo

“Extraordinary Measures,” which stars Brendan Fraser and Harrison Ford, could bring great exposure to Pompe disease, say researchers. movieweb.com
(Full-size photo)

Being only 5 years old, Clay Bowden isn’t aware of the drama surrounding the drug that keeps him alive. But he can watch the movie.

“Extraordinary Measures,” the new film starring Harrison Ford and Brendan Fraser, tells a fictionalized account of how a real drug came to market in 2006 and saved hundreds of youngsters, including Bowden, afflicted with a rare metabolic disorder called Pompe disease.

And while movie trailers boast that the film is inspired by a true story – Fraser’s character, John Crowley, is real – the actual drug development occurred at Duke University by scientists who look and behave nothing like the crotchety loner Ford plays.

“I’m incredibly proud of what we’ve done,” says Dr. Priya Kishnani, a pediatric geneticist who helped lead clinical trials at Duke that resulted in the drug’s regulatory approval.

And while she’s frustrated Duke was written out of the movie, Kishnani said she’s pleased attention is being drawn to Pompe disease, which had been a childhood death sentence before the drug was available.

In the movie, credit for the drug’s development goes to Ford’s character, Dr. Robert Stonehill, a make-believe angry scientist whose genius is unappreciated until Crowley arrives.

Crowley, in both the film and real life, is a Harvard-educated bio-tech executive and father of two children diagnosed with Pompe. After they grew sick, Crowley quit his job and raised venture capital to sponsor what he thought was a promising drug candidate.

In fact, the drug Crowley backed never made it out of the laboratory. Instead, Genzyme, the pharmaceutical company that bought his start-up, pressed ahead with a more effective therapy based on Duke’s science.

That treatment replaces an enzyme that people with Pompe disease do not produce at all, or at severely low levels.

The enzyme prevents the buildup of a starch called glycogen, much like insulin prevents the buildup of glucose. As glycogen accumulates, it degenerates muscles.

Babies born with Pompe were destined to die within their first year. It was also eventually fatal to older children and adults whose disease surfaced later.

Duke researchers began pursuing treatments for Pompe disease in the 1990s, led by Dr. Yuan-Tsong Chen, a pediatric geneticist who used DNA technology in the ovary cells of Chinese hamsters to produce the missing enzyme.

The Duke team first tested the drug in quail that were so impaired they couldn’t stand or even roll over. The enzyme worked, and one of the birds actually flew.

In 1999, Duke began clinical trials in humans. Three children were enrolled; one responded well and the other two eventually died. Given the lethal nature of Pompe, those odds of survival were a huge improvement.

Overwhelmed with interest from desperate parents – including Crowley, who breached ethical considerations with unsuccessful attempts to get his children enrolled in the early tests – Duke led a second trial. Again, it showed promise.

“With the experience we gained from the earlier trials, we learned several lessons,” Kishnani says. “The earlier we started, the better the results.”

The third and largest clinical trial had the strongest results, and the Food and Drug Administration granted approval for the drug, called Myozyme, in 2006.

Kishnani says it was a heated time. Parents throughout the world called Duke or simply showed up in Durham seeking the enzyme infusions to save their children.

But the drug was difficult to make and in short supply, so it was reserved for clinical trial participants and a few babies who would otherwise have died.

Clay Bowden, of Cumberland County, N.C., was among the lucky few. Born before the drug was approved, but too late to participate in the clinical trial, Clay received Myozyme at the age of 3 months under a so-called compassionate use waiver from the FDA.

Now five years later, he makes a two-hour trip with his grandmother, Rebecca, from Linden, N.C., to Duke every week for infusions.

While Clay plays video games and watches movies, an intravenous line drips Myozyme into his body through a port on his stomach. It’s a regimen he’ll keep for the rest of his life.

A spirited kindergartner, he has a speech impairment and wears braces on both feet. But he plans to play T-ball again this spring.

“It’s a miracle for him,” Rebecca Bowden says.

Kishnani says work on the drug continues, as researchers try to find ways to boost its effect and get it to babies sooner.

The Duke team is also working to get Pompe disease added to the battery of metabolic disorders screened for at birth.

The movie, Kishnani says, could help in that effort.

“It brings about great exposure,” she says, even if it doesn’t tell the full story.


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