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Why Gene Therapy Still Hasn't Produced Forecast Breakthroughs

by Sharon BegleyWall Street Journal
February 21st, 2005

Katherine High
Katherine High

Katherine High thought she was making progress. She and her team had managed to take the human gene that produces Factor IX, a blood-clotting substance that people with hemophilia lack, and slip it into a harmless virus called AAV. The virus played Trojan horse, carrying the gene into lab mice and dogs. There, it worked its way into the animals' DNA and produced enough clotting factor to cure their hemophilia.


But when Dr. High, a professor of pediatrics at Children's Hospital of Philadelphia, and her colleagues launched human trials in 2001, the picture darkened. They injected the gene-carrying viruses into the livers of seven patients. Two produced measurable amounts of Factor IX, 3 percent and 12 percent of the normal level. But within a few weeks the levels became undetectable, Dr. High reported last year. The patients' immune systems had apparently killed the cells containing the inserted gene.


Dr. High had some ideas about how to fix that. But in May the biotech company sponsoring her work bailed out.


So it has gone for gene therapy, the great hope of the genetic revolution. The idea was simplicity itself: Use a safe virus to carry a healthy gene into the cells of patients who suffer from a genetic disease -- sickle cell, cystic fibrosis, hemophilia -- because their own version of that gene is kaput. Rather than treating the downstream effects of the broken DNA, gene therapy would fix what was actually broken.


If only. Since 1989 there have been more than 350 gene-therapy trials world-wide intended to help patients. Of the thousands in the trials, about a dozen, all children with a rare immune disorder, have been cured.


"There was so much optimism and naivete," says Donald Kohn of Childrens Hospital Los Angeles, who conducts gene-therapy trials with bone-marrow cells. "What worked so well in mice in the 1980s -- the reason for the optimism -- turned out to be very difficult to translate into humans."


For one thing, in mice the target cells tend to divide constantly and "easily take up the foreign gene," he explains. It wasn't unusual to get the gene into 50 percent of certain mouse cells. Not so in humans, where 0.1 percent is a triumph. In fact, in what seems like sheer spite on nature's part, human bone marrow cells that take in the foreign gene are also the ones that function for only a few weeks, leaving no lasting therapeutic benefit, explains Dr. Kohn; human cells in which the gene has a good chance of functioning over the long run resist taking it in.


No wonder the field seems cursed.


In 1999, 18-year-old volunteer Jesse Gelsinger died when he experienced a fatal inflammatory reaction to gene therapy. Last week the U.S. Justice Department announced a settlement with the scientist who ran that trial.


In 2002 and 2003, three little boys in what had been gene therapy's one successful trial developed a leukemia-like disease. The children had X-linked severe combined immunodeficiency, or X-SCID, a potentially fatal disorder related to "bubble boy" syndrome that leaves victims with essentially no immune system. The inserted DNA had found the one-in-a-million spot that activated a cancer-causing gene.


Few gene-therapy trials end in tragedy, but most end in failure. In many cases, the inserted gene stops working. In the first trial of its kind, in 1993, Ronald Crystal of Cornell University's Weill Medical College used a cold virus to ferry into patients' lung cells a healthy gene meant to replace the one that causes cystic fibrosis. That part went fine. But the gene stopped working after a week. The patients' immune systems had noticed the virus and tore apart the cells harboring it and its DNA cargo.


Now gene therapy has encountered its most daunting obstacle yet: the impatience of biotech companies. The single-gene diseases it first targeted are almost all "orphan diseases," notes Dr. Crystal, meaning they claim no more than a few hundred victims at any one time. With the prospect of such a tiny market, companies sponsoring gene-therapy trials are increasingly unwilling to stick with any that encounter the slightest glitch.


"Gene therapy has been 'five years away' for 20 years," says biotech executive John Crowley, chairman and CEO of Amicus Therapeutics, North Brunswick, N.J. "When you have concerns about the economics of this, and add failure after failure, venture capitalists are saying there are better places to put our money."


Partly as a result, gene therapy is shifting to complex (and common) diseases. Of the gene-therapy trials now under way, 60 percent target cancer. Only 10 percent aim to treat the rare, single-gene diseases for which the technique was invented.


And today's dreams are much more modest. Gene therapy for cancer would induce a patient's immune system to kill tumor cells by tagging them with molecules that say "foreign." But because some cells would escape this fate and keep replicating, gene therapy would almost surely be just another arrow in a quiver that includes surgery, radiation and chemotherapy, says Dr. Crystal. Assuming it worked at all.


The unhappy history of gene therapy offers a cautionary tale for stem-cell research. It, too, is already curing lab animals. It, too, looks as though it can't miss. That's what they said about gene therapy.



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