In the latest attempt to conquer the leading genetic killer of children, researchers at the Johns Hopkins Medical Institutions have inoculated their first patient in a trial of a gene therapy for cystic fibrosis.
The scientists hope to overcome problems that have plagued researchers at other universities who have also used gene therapy to fight the disease, which afflicts about 30,000 children and young adults. Patients suffer from abnormally thick, sticky mucous that clogs their lungs and produces fatal infections.
The gene therapies have employed a common strategy. Scientists equip viruses with copies of genes that instruct cells to perform activities vital to healthy lungs. The viruses act as Trojan horses, carrying the genes inside cells while infecting them.
Scientists involved in six previous efforts have used a weakened form of the common adenovirus to carry mucous-fighting genes inside respiratory cells. In its unaltered state, the virus causes colds and flulike symptoms.
Although the trials have not been declared outright failures, many did not deliver the gene to adequate numbers of target cells. Several provoked inflammation and triggered immune system attacks that killed cells carrying the healthy genes.
Dr. Terence Flotte, an assistant professor of pediatrics at Hopkins, said the latest trial could be a turning point in the hunt for a successful gene therapy because it employs a different virus -- one that resides naturally inside most people without ill effects.
The Hopkins researchers have chosen the adeno-associated virus (AAV) as their delivery system, hoping it will prove "a nontoxic way to transfer genes into these cells without triggering inflammation," Dr. Flotte said. The first patient in the study, a young woman who asked not to be identified, was inoculated last week. Researchers plan to inoculate a total of 12 people over the next year in a trial that will measure safety and success in introducing the genes.
Another volunteer, 21-year-old Augusta Brotzman of Plattsburgh, N.Y., said she enrolled in the trial knowing that the therapy -- new and untested -- is unlikely to ease her symptoms. But she wanted to help fight a disease that killed her brother and many friends she made while hospitalized.
Fighting for her friends
"I'm so sick of CF," said Ms. Brotzman, whose cousin is also afflicted. "You grow up with your friends dying all the time. You want to do it more for them than for yourself."
She is to receive the therapy in January.
The disease once killed the vast majority of sufferers by the time they reached their teens. Many now survive into their 20s and 30s, with small numbers living beyond that. Longer survival is attributed to better antibiotics and physical therapy.
The Hopkins trial is limited to adults with mild to moderate forms of the disease. Choosing relatively healthy people should give scientists an easier time distinguishing side effects from disease symptoms.
Physicians use an ultrathin tube to inoculate both nostrils and a small section of lung. They begin with extremely small doses that will become progressively larger with each new patient, the last of whom will get a dosage about 300 times larger than the first.
Even at that point, the therapy would probably be too modest to produce a therapeutic effect.
"Our best-case scenario is that we'll be able to move up to a dosage level where we will efficiently transfer the normal gene without any side effect," said Dr. Flotte. "If we can do that, then it can set the stage for a study that will test the therapeutic effect of the gene."
The trial is being led by Dr. Flotte; Dr. William Guggino, director of Hopkins' Gene Therapy Center; Dr. Beryl Rosenstein, the hospital's CF clinical director; and researchers at Targeted Genetics, a Seattle biotechnology firm.
Johns Hopkins licensed rights to produce the vector -- the gene-delivery system -- to Targeted Genetics in return for royalties.
How project started
The collaborators began work soon after the discovery in 1989 of the gene that causes cystic fibrosis. Afflicted people carry two flawed copies of the gene that, in its healthy state, produces a protein that helps transport salt out of cells lining the lungs.
Once outside the cells, the salt attracts water that, in turn, thins mucous.
"We don't know yet if the AAV vector will allow therapeutic amounts of the protein to be produced," Dr. Guggino said. "But laboratory and animal studies indicate it is capable of doing so."
"The AAV have their theoretical advantages but you really don't know until you get them into the patients," said Dr. Robert J. Beall, executive director of the Bethesda-based Cystic Fibrosis Foundation, which is cosponsoring the experiment.
Volunteers spend two weeks in isolation after their inoculation. Later, doctors study cell samples to see how frequently the genes reached their target cells. Other tests will help determine if salt and water are moving across nasal membranes.