In 1989, scientists studying cystic fibrosis made a historic discovery by identifying a stretch of flawed DNA that causes the disease. As well as helping researchers solve the biological mysteries of the inherited illness, this find opened the door to the revolutionary idea of gene therapy-curing the disease by inserting into patients' lung cells correct copies of the gene.
Today, one clinical trial of gene therapy to cure cystic fibrosis is under way at the National Institutes of Health. On Aug. 4, the Food & Drug Administration approved another, at the University of Pennsylvania. Meanwhile, companies are racing to capture the potentially lucrative gene therapy market. "The field has moved so quickly, it's remarkable," says Dr. Ronald G. Crystal, chief of pulmonary medicine at New York Hospital-Cornell Medical Center, leader of the NIH trial, and co-founder of gene therapy startup GenVec in Rockville, Md. Many researchers are confident that one day gene therapy will render drugs such as Genentech Inc.'s DNase obsolete.
TRICKY PROCESS. That doesn't mean that a genetic cure for CF is imminent. "We are still in the very early days," cautions Dr. Richard C. Boucher, director of the division of pulmonary diseases at the University of North Carolina at Chapel Hill (UNC). Still, sci- entists know that CF is caused by a defect in a protein that leads to the accumulation of mucus in the lungs. The mucus makes breathing difficult and breeds infections. If doctors slipped in a normal gene, inducing cells to make the correct protein, they could prevent the buildup and produce a cure.
The trick is inserting the gene. Four years ago, taking his cue from French researchers who had snipped out disease-causing genes in viruses of the pneumonia family, Crystal devised a plan. Since these adenoviruses do infect lung cells and carry in their own genes, why not splice in the CF gene and use the emasculated virus as a delivery truck? Animal experiments proved the scheme worked well enough to begin human trials. So on Apr. 17, Crystal dripped the engineered adenovirus into the lungs of the first CF patient. Genetic Therapy Inc. in Gaithersburg, Md., and Genzyme Corp. in Cambridge, Mass., are awaiting FDA approval for similar trials. Meanwhile, GenVec, buoyed by an investment from Genentech worth up to $17 million, is refining its system and planning more elaborate trials.
The adenovirus delivery system does pose risks. It retains a hunk of original viral DNA and seems to provoke the immune system. The first NIH patient to receive a dose close to that needed to actually fight the disease suffered significant inflammation in the lungs. "We now have to go back to lower doses and figure out the mechanism," says Crystal. In addition, adenoviruses don't splice genes into cells' own DNA. Instead, the added genes are gradually chewed up by the cells' trash system.
MAGIC BULLET? As a result, the gene must be reintroduced every few weeks or months. That's chancy since the body's defenses might begin attacking the virus. So researchers are trying new strategies. One of the most promising, still in development, enlists an ally called an adeno-associated virus. This unusual beast inserts its genes into the DNA of lung cells without causing discernible infections--and might deliver the CF gene without provoking an immune-system response. "There's a lot of excitement that this might be the magic bullet," says researcher Richard J. Samulski, director of the gene therapy center at UNC. Researchers at Johns Hopkins University and Seattle's Targeted Genetics Inc. hope to start clinical trials by the end of 1994.
A few scientists are avoiding viruses and delivering genes wrapped in or attached to fat molecules. Skeptics doubt this method will prompt cells to make enough of the correct protein to treat the disease. But unpublished experiments by Robert J. Debs of the University of California-San Francisco and researchers at San Francisco-based Megabios indicate that it is an "extraordinarily powerful system without the problems of viruses," Debs insists.
In short, "it's a horse race," says Samulski. And the prize is huge: fame, sales that could hit $600 million a year, and the chance to end the suffering of patients. Those payoffs have attracted millions in funding from the government, venture capitalists, and companies--enough to lay the foundation of gene therapy for other diseases. Predicts Hal Broderson, acting CEO of GenVec: "The 1990s will bring a new era of genes as drugs."