In the United States, no hereditary illness takes a greater toll than CF. One in 2,500 newborns is afflicted, and most die before turning 30. Some 12 million Americans-5 percent of the population-carry a single copy of the culpable gene, but only those with two copies develop the disease. The dynamics of cystic fibrosis are no mystery. In healthy people, a protein called CFTR provides a channel by which chloride (a component of salt) can pass in and out of cells. CF sufferers have a defective copy of the gene that normally enables cells to construct that channel (the socalled CFTR gene). As a result, salt accumulates in the cells lining the lungs and digestive tissues, turning the surrounding mucus into a sticky, suffocating paste. Slapping and pounding can help dislodge mucus from blocked airways, and antibiotics can control the incessant respiratory infections. But nothing stops the gradual destruction of the victims’ lungs.
Until 1989, the prospects for arresting this process seemed dim, but the discovery of the mutation responsible for cystic fibrosis raised a tantalizing possibility: if someone could synthesize normal copies of the CFTR gene and transfer them into a patient’s wayward cells, then the cells might start functioning properly.
In 1990, two scientific teams showed that the process worked in a test tube. In concurrent experiments, Dr. James Wilson of the University of Michigan and Dr. Michael Welsh of the University of Iowa succeeded at splicing the normal CFTR gene into disabled cold viruses. The viruses were essentially sterile and theoretically incapable of causing illness. But they made ideal delivery vehicles, for they retained their ability to glom onto respiratory cells and deposit their genetic material inside. As everyone had hoped, defective cells turned healthy when infected in a test tube. And when other lab studies showed that the treatment was safe in rats and monkeys, researchers started seeking government approval for a human trial.
Last December, a National Institutes of Health advisory panel endorsed proposals from three teams-Wilson’s, Welsh’s, and one led by Dr. Ronald Crystal of the NHLBI-and this month Crystal became the first to treat a patient. The initial volunteer received just over four teaspoons of medication through nose drops and a bronchoscope. A second patient started the same regimen last week, and Crystal plans to treat eight more.
Along the way, he hopes to answer several basic questions. The most pressing is whether the treatment is safe; he needs to prove that the virus won’t somehow cause disease or inflammation and that it won’t spread its cargo beyond the respiratory system. In addition, he wants to determine how readily patients’ cells will respond to the treatment, and for how long. If the treatment works, cells that acquire the new gene will manufacture their own chloride channels and start excreting salt normally. But no one knows what dose of virus is needed to infect a given number of cells or just how long the therapeutic effect will last. Because the cells that line the tissues are continually replaced, the effect will not be permanent. But Crystal hopes that at high doses, each round of treatment willbringa couple of months’ relief. There’s also a danger that after repeated exposures, patients’ immune systems will learn to foil the virus before it can do its job. That problem hasn’t surfaced in animal studies, and Crystal believes that he can administer the virus in large enough doses to survive even a robust immune reaction.
In a sense, this bold experiment will succeed even if it fails. Scientists have already shown that CF sufferers’ cells will respond to gene therapy. The challenge is simply to find a practical way of applying it. “I chose this virus because it’s been studied,” Crystal says, “but it’s not the only possible system.” Scientists are already conducting lab studies with other delivery vehicles-some based not on viruses but on microscopic fat capsules known as liposomes-and optimism abounds. “What we’re doing now may be very different from what we’ll be doing a couple of years from now,” says Beall of the Cystic Fibrosis Foundation. If the past few years are any indication, that’s putting it mildly.
