THE VIRGINIAN-PILOT
Copyright (c) 1996, Landmark Communications, Inc.
DATE: Thursday, October 10, 1996 TAG: 9610100313
SECTION: FRONT PAGE: A1 EDITION: FINAL
SOURCE: BY DEBRA GORDON, STAFF WRITER
LENGTH: 170 lines
Today, 20-year-old Jason Konkel is in Baltimore being a human guinea pig.
Doctors at Johns Hopkins medical center are testing the Virginia Beach man's blood and urine, peering into his lungs and shooting numerous X-rays and CAT scans of his chest. They are searching for any evidence of the microscopic viruses they injected into his nasal passages and lungs in January.
Those viruses carried a special cargo - a tiny snippet of cloned DNA, a gene - to deliver to Konkel's respiratory cells. Eventually the viruses - and Konkel's role in testing them - may be instrumental in curing the country's most lethal genetic disease in Caucasians: cystic fibrosis.
Konkel is participating in one of the few human trials of gene therapy in the world. He has volunteered knowing that the experiments have little chance of curing his own cystic fibrosis, and that they could even impair his somewhat-shaky health.
Ask him why he's doing it, and he has a simple answer: ``I'm tired of watching my friends die.''
Cystic fibrosis occurs when children receive a defective gene because both parents carry the trait for the disease. An estimated 30,000 Americans have the illness, about 200 in Hampton Roads.
The disease is characterized by frequent respiratory infections and malfunctioning of the pancreas.
Because of the defective gene, the cells that line the lungs absorb too much water. This dries out the mucous that helps protect the lungs against infection, making the mucous thick and hard to cough up. Bacteria grow in the mucous, causing numerous infections and leading to severe lung damage and eventually death.
When Dr. Thomas Rubio arrived at Children's Hospital of The King's Daughters to head its infectious disease department in the late 1970s, the life expectancy of a child with cystic fibrosis was about 15. Today, thanks to stronger antibiotics and new treatments, including lung transplants, that age has risen to 30.
Still, doctors can only treat the symptoms of the disease.
``Gene therapy has always been our definite hope,'' said Rubio, who treats most of the region's cystic fibrosis patients, including adults.
``We know transplants and anti-biotics are really only temporary things just to keep them going with the hope that there would be something better discovered.''
Those hopes got a boost in 1989, when scientists announced they'd located the gene responsible for cystic fibrosis.
A mutation in the gene - actually, there are more than 350 possible mutations on this one gene - prevents the release of an important protein that regulates sodium and chloride, salt, in certain cells, which causes the water absorption problems.
In recent years, thanks to the Human Genome Project, announcements of new genes have come almost weekly. In most cases, however, the practical uses of gene therapy in humans are still decades away.
Cystic fibrosis is an exception.
Its strong national advocacy group, the Bethesda, Md.-based Cystic Fibrosis Foundation, has provided both the funding and the political pressure to push research on the cystic fibrosis gene further than nearly any other such research, said William Kearns, an assistant professor of pediatrics at the Center for Pediatric Research, a joint program between Eastern Virginia Medical School and Children's Hospital.
Kearns, who has a joint faculty appointment at Johns Hopkins and EVMS, is a researcher in the Hopkins cystic fibrosis program.
By 1992 - a mere three years after the discovery of the gene - the first human trials were under way and a kind of euphoria permeated the cystic fibrosis scientific community.
It wouldn't last.
The problem lay in the major challenge of gene therapy: How do you get the normal gene into a cell so it can bind with the cell's own DNA, jumpstarting it to make the missing protein?
An injection doesn't work. And the technology necessary to ``transplant'' tiny pieces of a gene isn't available yet.
So scientists search for some sort of delivery system, or ``vector,'' to deposit genes into cells. In cystic fibrosis, they turned to an ``adenovirus,'' a simple cold virus, as the vector.
But early trials showed that the virus itself caused an inflammation in subjects' lungs, a potentially dangerous effect in someone who is prone to serious respiratory infections.
The adenovirus also stimulated the production of antibodies; so the next time the virus was used to carry a gene, the body would send out defenses to fight its entry.
Most disappointing was the news, published in the New England Journal of Medicine last year, that the virus only delivered the gene about 1 percent of the time - not enough to have any significant effect.
Clearly, a better vector was needed.
Kearns and the Johns Hopkins team thought they had one: an adeno-associated virus, or AAV, a naturally occurring virus that doesn't cause any known disease. Most people have already been exposed to it during their lifetime.
After years of testing in animals and test tubes, the Hopkins/EVMS team began clinical trials last November on 12 people, including Jason Konkel.
In the 11-page brochure that subjects in the Hopkins trial receive, one sentence is underlined: ``This is not expected to be a one-time cure for CF, and no medical benefit is expected for the subjects in this initial trial.''
Later, another sentence, not underlined, jumps out: ``The risk posed to you from the gene transfer virus itself is not precisely known.''
Jason Konkel read those two sentences a year ago and didn't hesitate a second. He signed up.
Konkel's participation was particularly important since the study called for relatively healthy cystic fibrosis patients over age 18. They're hard to find.
By age 18, most cystic fibrosis sufferers have had numerous bouts of pneumonia and other lung infections, resulting in severe scarring of their lungs.
Konkel had been lucky; he hadn't had any serious infections until age 13. Since then, his hospital stays had increased from once a year to every three months during the year before he began the Hopkins study.
Still, compared to most cystic fibrosis sufferers his age, he was pretty healthy. But participating in the study could change that. He could develop a reaction to the virus that, the brochure flatly stated, ``could impair his long-term health and well-being.''
More frightening was the possibility of long-term side effects from the virus inserting its DNA into the cells of his lungs, theoretically putting him at risk for lung cancer.
When Konkel read those warnings, his mind flashed on a vision of a 19-year-old girl, a gold wedding band on her finger, dying in the intensive care unit.
She was a close friend, engaged to another cystic fibrosis sufferer. But when she died two years ago - still unmarried - her fiance gave up on his own life, dying just a short time later.
It is for them that Konkel decided to ignore the risks and participate in the Hopkins study.
``I thought that, given the people I knew who had already passed away, the least I could do is take a little bit of pain, a little bit of problems in the future or now, sacrifice a few things for the people who have lost their lives with CF,'' he said.
Konkel has already sacrificed for the disease. The tall, gangly young man with the strawberry blond hair has been forced to give up career dreams of joining the Coast Guard and of becoming a flight attendant.
To participate in the study, he delayed entering college, where he plans to study hotel and restaurant management.
To him, disrupting his life for the weeks-long stays in Baltimore, undergoing the painful, probing medical procedures and taking great risks with what may already be a shortened life span, is no big deal.
His reaction is typical of cystic fibrosis sufferers, Rubio said.
``These patients are the most cooperative, the nicest people I can think of. From the moment they find out they have (cystic fibrosis), they say, `If there is something I can do to improve this condition, then I want to participate, even if it's only for research.' ''
Konkel is nearly finished with the first phase of the clinical trials, designed to test the effects of the virus itself. Phase II will involve higher doses of the virus/gene. It should start in about six months.
Even if the trials are successful, and the delivered gene actually stimulates the cell to produce the missing protein, it is not a one-shot cure. Patients will probably have to undergo the therapy every few months for the rest of their lives.
One of the study's researchers, William B. Guggino, professor of physiology and pediatrics at Johns Hopkins, said that so far, none of the study's subjects has had any adverse effects from the virus.
But they've received far too little of the virus and gene to know if the gene itself has had any effect.
Intellectually, Konkel knows that.
But, he said, something strange has happened since doctors squirted the salt-water solution containing the virus/gene into his lungs.
He hasn't been sick.
Even a stubborn fungus infection he'd had for two years has cleared up.
Coincidence?
His mother doesn't think so.
``He's been healthy ever since he started,'' Kathy Konkel said. ``In my heart, I know he has the real thing.'' ILLUSTRATION: Color photo MIKE HEFFNER/The Virginian-Pilot
Jason Konkel, 20, said he volunteered for painful gene therapy
experiments because ``I'm tired of watching my friends die.''
Graphica by VP
Source: CQ Researcher
Cystic Fibrosis Gene Therapy [For complete copy, see microfilm]
KEYWORDS: GENE THERAPY CYSTIC FIBROSIS by CNB