Gene therapy for rare cholesterol disorder.

A proposal to use gene therapy to treat a rare, inherited form of high blood cholesterol won approval this week from an advisory committee convened by the National Institutes of Health.

The proposed trial is the fifth gene therapy experiment to gain the NIH committee's blessings. It holds out hope for the roughly 100 people in the United States with familial hypercholesterolemia, which often causes a fatal heart attack before adulthood.

A team led by James M. Wilson at the University of Michigan Medical Center in Ann Arbor received the nod from the NIH Recombinant DNA Advisory Committee to administer genetically engineered liver cells to thee patients with familial hypercholesterolemia. The cells, taken from the patients' own livers, would contain an added gene that directs production of cellular receptors that sop up low-density lipoprotein (LDL) cholesterol -- the "bad" cholesterol -- from the blood-stream.

Patients with the most severe form of familial hypercholesterolemia are born lacking both of the usual two copies of the LDL receptor gene. As a result, their blood contains astronomically high cholesterol concentrations -- roughly four to five times the levels found in healthy individuals. Because of their cholesterol load, most of these patients suffer several heart attacks before they enter junior high school. They also develop thick, yellow flaps of fatty skin, called xanthomas, around their elbows and knees.

People born with one copy of the LDL receptor gene have abnormally high blood cholesterol but sometimes live into their 30s or 40s. Researchers estimate that roughly 5 percent of heart-attack patients under age 45 have this less severe form of familial hypercholesterolemia.

The standard treatments for both forms of the disorder are cholesterol-lowering drugs and plasmapheresis, in which a machine filters excess cholesterol from the patient's blood. But the drugs do not work well on patients who lack both copies of the LDL receptor gene, and plasmapheresis is only a temporary solution. Most patients end up having coronary bypass surgery.

"There really is no treatment of choice," says Wilson. "We hope to diminish the [cholesterol counts] of the gene therapy patients, so they might respond better to standard therapies."

He and his colleagues plan to surgically remove a slice representing 15 percent of each patient's liver, isolate liver cells called hepatocytes, and culture them in the laboratory. After using a crippled retrovirus to insert a gene for the LDL receptor into the hepatocytes, the researchers will reinject the engineered cells into the major blood vessels supplying the patient's liver. They hope some of the LDL-receptor-bearing cells will take up residence in the liver and reduce the patient's cholesterol level.

Wilson's group demonstrated last year that the gene therapy strategy works in Watanabe rabbits, which also accumulate cholesterol. Genetically engineered liver cells reduced the rabbits' blood cholesterol levels by an average of 30 percent (SN: 11/10/90, p.294). A separate team in Houston, led by Fred D. Ledley at Baylor College of Medicine, is using a marker gene to test whether transplanted hepatocytes reestablish themselves in the human liver (SN: 4/13/91, p.228).

"This is a well-thought-out proposal based on solid preclinical data," says NIH committee member Roy H. Doi of the University of California, Davis. Henry I. Miller, head of the Food and Drug Administration's biotechnology office, says the experimental treatment "should reasonably be expected to have a clinical benefit in these patients."

Wilson's team plans to begin treating the three patients as soon as the experimental protocol is evaluated by the FDA and signed by the NIH director.