Researchers into Duchenne MD take the fight personally

From the Los Angeles Times:

Rarely in life do the personal and professional become the bittersweet blend that Stan Nelson and Carrie Miceli experience every day.

At work, the medical researchers at UCLA painstakingly delve into the genetic underpinnings of Duchenne muscular dystrophy, the most common of childhood's lethal DNA-linked diseases.

At home, they treasure their family time with sons Calvin, 16, and Dylan, 9. Such time is precious. Dylan (pictured) was diagnosed with Duchenne as a toddler.

Miceli and Nelson don't dream of a cure for their youngest son. Heavily schooled in objectivity and neutrality, they are able to tolerate the often-creeping pace of science and yet savor its progress.

"We have a sweet, wonderful boy who is delighted with life," said Nelson, a former pediatric oncologist, now a genomics researcher. "One could spend one's life racing against the clock — and making that the focus of family life and of research life. I don't spend a lot of time dwelling on that."

The couple's goals are much more immediate. This year, Nelson and Miceli will open the doors of a Duchenne muscular dystrophy clinic at UCLA. It will serve approximately 350 boys — many of whom now travel out of state for treatment — offering specialized cardiac and neurological care as well as physical therapy and access to clinical trials.

The disease, which mainly affects boys, usually leads to death from lung disorders. But specialized care can add several years of life expectancy to the 25 years or so that is typical, doctors say.

"We're creating an infrastructure at UCLA that will live on in the future," Nelson said. "That's rewarding."

"It's all coming together in the last five years," said Miceli, an immunologist who studies the function of T cells, white cells that are crucial to immune system function. "I have no doubt that the course of the disease will be different for this generation of boys. We don't know how different. But we just have to go forward."

***

In the family room of their Los Angeles home on a weekday afternoon, Dylan is watching cartoons and eating a slice of cantaloupe. Both he and Calvin are creative, and their paintings, sketches and poems fill the home. Dylan's repertoire includes a poem on a wall near the kitchen titled "In My Heart."

In my heart, I feel I can fly.

A whirlwind of boy energy, he soon abandons the cartoons to take on his mom in a backyard game of handball, his favorite sport. Stocky, with blue eyes and a mop of dark hair, he smacks the ball against an ever-expanding smudge on the stucco exterior. Already, he moves with a hint of the gait problems that boys with the disease develop as they approach their teen years.

A power scooter on which Calvin has painted Star Wars characters sits just inside the front door, available should Dylan need to conserve his strength. But Dylan ignores the scooter today. He bounces the ball to his mother.

"Whoa, Mom! How are you getting so good?" Dylan says, keeping up a steady monologue.

"I may have a sleepover this weekend. OK?"

Smack.

"Mom, why can't I take a handball class?"

Smack.

"Mom, can you find a comic camp?"

Nelson and Miceli recently installed a chair lift at home, to gently introduce Dylan to the concept that he will one day need it. But for now their home life is a bubble. Dylan knows he has a muscle disorder but does not understand the severity of the disease.

"He's coming to realize he is a little different," Miceli said. Still, she said, "he is the happiest boy ever."

***

Duchenne muscular dystrophy is perhaps best known as the disease targeted by comedian Jerry Lewis on an annual Labor Day telethon. It's caused by any of a number of mutations that occur in the Duchenne gene, located on the X chromosome. That gene is essential to muscle cell structure and function, and the mutations disrupt production of a protein called dystrophin, causing the muscles, plus the heart and respiratory systems, to deteriorate.

The disease typically affects only boys because males have only one X chromosome, meaning those with the mutation have no healthy version of the gene. About 1 in every 3,500 males is born with the mutation.

The couple gradually began working together on research to understand the disease. Nelson and Miceli knew Duchenne wasn't curable. But they were dismayed by the lack of research momentum.

The gene had been discovered in 1986, but no treatments were in clinical trials. Only a few comprehensive Duchenne clinics existed in the country, and a mere handful of scientists were aggressively working on the disease.

"We felt like we came upon an area that was not being sufficiently pursued," Nelson said. "Kids were diagnosed and parents were told, 'This is the course of the disease, and you can't change it that much.' "

Few parents willingly accept that prognosis. Nelson, 49, and Miceli, 48, were in a position to challenge it.

"They are both very prominent scientists in their respective fields," said Melissa J. Spencer, an associate professor of neurology at UCLA who was researching Duchenne when Dylan was diagnosed. "It's not that they weren't shocked and emotional. But their attitude was still, 'Let's do something positive here.' "

***

With their far-reaching connections in the science world, Nelson and Miceli were able to reach out to top scientists, asking for information and input. They've persuaded researchers to look at Duchenne in a different way, even urging colleagues in other fields of science to propose novel ways to treat it.

Scientists hope to shepherd a handful of therapies to the market that might improve quality of life for boys and young men with the condition, maybe even extend life.

One of the more promising avenues has developed around a class of drugs, still in development, that uses artificial molecules to find one of the Duchenne mutations and begin mimicking ungarbled DNA. The DNA patch allows the gene to produce some dystrophin, just not perfectly — similar to a car that is out of alignment but still runs.

Human trials of the treatment, called exon skipping, will begin soon.

Exon skipping also is expected to be tested in other genetic disorders as a prototype for personalized, molecular medicine. The idea is to change the therapeutic patch to fit whatever gene mutation is targeted.

The therapy could dramatically improve a patient's quality of life, Spencer said.

Further, Miceli has helped identify a protein that appears to cause some of the muscle inflammation that is a hallmark of Duchenne.

Other advances include gene therapy — inserting a healthy copy of the mutated gene into the body to treat disease — that will begin human trials this year or early next year at the University of Washington.

But, as always with Duchenne, new obstacles surface. This spring, in one of the first human trials targeting the production of dystrophin, an oral drug called ataluren failed to produce measurable improvement in boys with a specific type of mutation.

"Duchenne's is a really tough nut to crack," said Dr. Edward Kaye, vice president of clinical research at Genzyme Inc., which is co-developing ataluren. "The people who succeed in this field are not necessarily the most intelligent. They're the people who will hang in there."

***

Nelson and Miceli spend about half of their work hours on Duchenne while still pursuing their original areas of research. Along with Spencer, they're co-directors of the Center for Duchenne Muscular Dystrophy at UCLA, in which the clinic will be based. The last major step before the clinic opens is the hiring of a director.

Nelson said anything that would help even a subset of boys with Duchenne would be an achievement. "People are focused on a cure," he said. "The likelihood is that we won't have cures but we will have effective treatments."

And if something comes along to help their son?

"We'd love it if that occurs," he said.

"It's not only about my kid," Miceli said. "Helping him and helping others are parallel goals. There is some comfort in paying it forward. If that's the best I can do — OK."

They spend a few minutes each morning and evening sitting with Dylan and gently stretching the muscles in his legs, arms and torso. He wriggles constantly and enjoys yelling "ouch," even though the manipulation doesn't hurt. In truth, Dylan is just aching to be free, on to the next ballgame or episode of "SpongeBob SquarePants."

"He's always energetic and running around, and has so much to say," said his brother, Calvin.

The family has a "self-expression" poem by Dylan framed just inside the door where he bangs the handball against the wall.

Dylan is a yellow happy. Dylan is a sunny day.