Roanoke Times
Copyright (c) 1995, Landmark Communications, Inc.
DATE: SUNDAY, May 30, 1993 TAG: 9305300112
SECTION: NATIONAL/INTERNATIONAL PAGE: A-2 EDITION: METRO
SOURCE: MALCOLM RITTER ASSOCIATED PRESS
DATELINE: CANTON, OHIO LENGTH: Long
Her brown ponytail tumbling out behind her baseball cap, Cindy Cutshall, 11, chases pop flies. She's been at it for a good half-hour on a warm and humid day, but no matter. She wants more fly balls to chase - more, more.
"She can do two hours of basketball on a court, whereas she couldn't do five minutes before," her mother says. "She can swim, she can play baseball. It's amazing."
An hour's drive away, near Cleveland, 6-year-old Ashi DeSilva boots a huge yellow ball with her "Beauty and the Beast" tennis shoes. Her face framed with black curly hair, she giggles as the ball returns and bounces off her head.
"To see her running around, knowing what she was like when she was ill, it's like a miracle," says her father. "It's absolutely a miracle."
These two little girls, says Jennifer Howse, president of the March of Dimes Birth Defects Foundation, are "the pioneering patients of our time" - the first two people in the world to benefit from gene therapy.
They were born with a defective gene that could not tell their bodies to make a critical enzyme. Without that substance, blood cells called T cells died off, crippling the disease-fighting immune system and leaving them vulnerable to potentially fatal infections.
But it was their good fortune to live at a time when scientific advances came at lightning speed. In a few short years, gene therapy - the use of transplanted genes to treat disease - went from a theory to a reality.
The idea was to equip as many remaining T cells as possible with a working gene to let them make the missing enzyme. But no one - not the girls, not their parents, not the doctors - knew if it would work.
Bruised by a touch
Ashanthi DeSilva, as Ashi formally is known, was born in Sri Lanka in September 1986 and came with her family the next month to the United States. Then her troubles began.
At about 2 months old, she began to get recurring chest and ear infections, with what seemed to be a constantly runny nose. She just could not overcome her colds. She was continuously on antibiotics.
It got worse. She was too weak to walk across the living room, recalled Van, and "she was so thin you could see her ribs."
Ashi repeatedly was misdiagnosed, but soon after her second birthday, Raj and Van finally learned the truth: Ashi had an extremely rare genetic disease called ADA deficiency, the lack of an enzyme called adenosine deaminase. It could kill her.
An experimental drug, PEG-ADA, saved Ashi's life. The diarrhea and vomiting stopped. Her appetite came back. She began to put on weight and grow.
But she still was tired and sickly, with frequent colds and flu, and her nose still ran constantly. One Saturday morning, her supply of blood platelets was so low that she bruised to the touch.
Her doctor sent samples of her blood to the National Institutes of Health. Scientists there were investigating whether ADA deficiency could be cured by giving patients new genes, he explained.
It was called gene therapy. It might work. Someday.
"He said, `Not in our lifetime, Van. Don't build up your hopes,"' Van recalled.
First therapy didn't work
Words tumble out at an adolescent's urgent pace as Cindy Cutshall conducts a breakneck tour of her photo album ("Look! We rode a camel at the zoo. . . . Look! A smurf. . . . Do you know there was a zebra that came up to our car?")
In one photo of a group of children, her finger flits from one face to another: "He's got it, he's got it, I've got it, he's got it . . ."
For Cindy, "it" showed up unusually late in life, around age 3, as sinus infections that progressed to pneumonia about six times a year.
She responded rapidly to antibiotics, so doctors "didn't think a whole lot about it. None of us did," recalled her mother, Susan, a nurse.
But at age 4, a hip infection forced Cindy into surgery and four weeks on antibiotics. Just two weeks after that was over, she got yet another sinus infection. Her pediatrician referred the family to an immunologist who diagnosed ADA deficiency in May 1987.
With PEG-ADA, she became sick less often and avoided serious infections altogether. But as with Ashi, the disease drained her of energy.
When Cindy's doctor mentioned he was sending blood samples to the National Institutes of Health to help them develop gene therapy in a decade or two, Susan said, "We didn't think much of it."
Successful experiment
The future came quickly - first for Ashi, then for Cindy.
In May 1990, two researchers from NIH met with Raj and Van in Cleveland to discuss trying a new experimental therapy on Ashi.
"They started talking about this gene therapy and genes, things we didn't understand at all," Raj recalled. "It was like trying to teach a kid advanced calculus."
"For me," said Van, "it was going to work. I just kept on believing it's going to happen. She's going to get chosen . . . I was praying it would happen, it would happen, it would happen."
"I just kept telling her, forget it. It's not going to happen," Raj said.
But four months later, Raj and Van entered a room at NIH to sign a consent form for Ashi's gene therapy.
Raj had doubts. It seemed risky, and he quizzed scientists at that meeting about results of past research. But, in the end, the chemical engineer from Sri Lanka realized his dilemma could not be solved by data.
"They answered the questions as best they could. You got the gut feeling they were honest and straightforward, not holding anything back," he said.
He signed.
Later that day, doctors withdrew some blood from Ashi so the T cells could be equipped with a new ADA gene. On Sept. 14, 1990, just 12 days after Ashi's fourth birthday, the treated cells were infused back into Ashi's veins.
The procedure was repeated seven times in the next year and three times after that, in an attempt to fix as many T cells as possible. She received PEG-ADA injections in tandem with the gene treatments.
Meanwhile, Cindy Cutshall endured the same process, starting in January 1991. And everyone waited to see what would happen.
The waiting was not protracted.
The difference in Ashi was dramatic. Her runny nose dried up. When the whole family got the flu, Ashi got over it first. Shedding her lethargy, she asked for roller skates and became as boisterous as a young girl should be.
Now she runs into the living room and spots her father, in an easy chair. She grabs his arms and drives her head into his chest like a determined, 76-pound defensive lineman. After a few minutes of tussling, she runs out.
"It's made her whole," Raj says. "PEG-ADA saved her life, but gene therapy gave her life."
Growing again
Cindy's energy returned, as well. She's playing in a softball league now, and she's seriously into baseball. She has uncounted baseball cards in her album. With great earnestness, she instructs a perfect stranger to grunt "Unnnh!" like an umpire when she throws or catches a strike.
In two years, Cindy has had only one sinus infection, and that was the only time she has needed antibiotics. She's maintaining her weight, and is growing again; the summer after she began gene therapy, her feet grew two sizes.
Cindy still is about a head-and-a-half shorter than a typical 11-year-old girl, and "it bugs her real bad," Susan says.
Susan's words of consolation: "You're OK. And you're here."
by CNB