The fix sticks – lasting success for gene therapy – special issue: 1994 – the Year in Science
Mark Caldwell
Gene therapy, for all its enormous promise, has been frustratingly slow to deliver. Since the late 1970s researchers have been itching to use the new biotechnological tools at their disposal to replace defective genes and cure a range of once-intractable diseases. But they’ve had a hard time getting everydiing to work. As of the beginning of 1994, no one could yet claim to have fixed a broken gene in a human, ameliorated the disease it caused, and, most important, kept the repair working over the long term.
Last April, however, a team from the University of Pennsylvania described how a year and a half earlier they’d treated a 28-year-old French-Canadian woman with a rare disease that causes astronomical cholesterol levels. The disease, familial hypercholesterolemia, is caused by a gene mutation that disables a protein, called an LDL receptor, found on the outside of liver cells.
The job of this protein is to snag – and thus remove from the bloodstream – the low-density lipoproteins (LDLS) familiar to everyone as the “bad” cholesterol associated with clogged arteries and heart attacks. The woman treated by the Pennsylvania team had suffered a heart attack at age 16 and had had coronary bypass surgery at 26. Two of her brothers, who had also inherited the defective gene, had died of heart attacks in their twenties. Cholesterol-reducing drugs did this woman no good at all – these drugs work by activating the genes that produce receptor proteins, and thus cause the cell to produce more receptors. In her case, though, since the receptors were defective in the first place, increasing their numbers was useless.
The approach taken by the team, which was led by geneticists James Wilson and Mariann Grossman was conceptually simple. The first step was to surgically cut out 15 percent of the woman’s liver and thereby obtain some 3.2 billion living cells, all presumably with the scrambled receptor gene. The next step was to repair the gene. For this the team used a retrovirus, which doesn’t merely infect cells but actually installs its genes among the cells’ own, making them part of the cells for life. “We gutted the virus of all its harmful genes,” Wilson explains, and fitted it with a normal copy of the human LDL-receptor gene. They then added the virus to dishfuls of their patient’s liver cells, hoping it would sphce the remedial gene into the cells’chromosomes.
The process worked in about a fiftb of the cells. Three days after the liver surgery, the researchers pumped millions of these repaired ceffs back into their patient, via a tube put into a vein that emptied into her liver. Then they waited to see if some of the cells would colonize the liver tissue, reproduce, and bgin removing LDL cholesterol.
To Wilson’s delight, the patient’s LDL levels quickly dropped 17 percent. For the first time, she began responding to cholesterol-reducing drugs, further lowering her LDL levels. And the repair held up. By last April, when the researchers published their results their patient’s condition had remained steady for 18 months. It hasn’t changed since.
“Her heart and b d levels are still stable,” says Wilson, “and her spirit is good.” The team has since treated five more people.
The one obvious drawback to this approach is that it puts patients through major surgery. That’s why the team is eyeing another type of virus, called an adenovirus, as an alternative shuttle for the remedial gene. “If you dump this virus in the blood, it naturally goes to the liver,” Wilson says, “and that’s a hundredfold more efficient than transplanting cells.”
Unlike a retrovirus, though, the adenovirus wouldn’t provide a recipient with a permanent remeddy – it doesn’t deposit its genes into a cell’s chromosomes, so the beneficial gene would be lost to future cells. But the turnover time in liver cells is so slow that the therapy might still last a year or more, and it could easily be repeated. Now, if this virus can be tinkered with and tamed – in its present state it causes fulminant hepatitis – patients could look forward to a much easier fix.
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