Gene therapy takes on cholesterol defect.

In the first account of successful gene therapy published in a scientific journal, a U.S. team reports it has partially corrected an inherited form of high cholesterol.

Their patient is a French Canadian woman whose medical history is a chilling reminder of the limits of conventional medicine. This woman suffered a heart attack at age 16. She underwent bypass surgery at age 24. Yet her condition continued to worsen.

In June 1992, the woman made medical. history by undergoing experimental gene therapy at the University of Michigan. Medical Center in Ann Arbor. James M. Wilson and the other researchers responsible for that procedure have since moved to the University of Pennsylvania Medical Center in Philadelphia. In the April NATURE GENETICS they describe a moderate lowering of cholesterol concentrations in this patient's blood with gene therapy, an effect that has lasted 21 months.

This work represents "a genuine step forward in the slow road to successful somatic gene therapy," comments David Weatherall in an editorial that appears in the same issue. "It suggests that, ultimately, it will be possible to correct genetic diseases which are expressed primarily in liver cells; says Weatherall, of the University of Oxford in England.

This patient and others with the rare disorder known as familial hypercholesterolemia inherit mutant versions of genes that code for a liver cell receptor. With the resulting flawed receptors, liver cells can't clear low density lipoprotein (LDL) cholesterol from the bloodstream.

LDL cholesterol sticks to artery walls, clogging the vessels. Particularly at risk are people, like Wilson's patient, who inherit two copies of the defective gene and thus have astonishingly high concentrations of LDL cholesterol.

The procedure, which was approved by federal health officials, involves removing about 10 percent of the patient's liver and culturing those cells in the laboratory.. The researchers used a crippled virus to insert healthy copies of the cholesterol-lowering receptor gene into the cultured liver cells. They then injected the cells into the patient's bloodstream (see illustration).

Some of those cells set up shop in the liver, where the inserted genes turned on and started directing the production of the normal cholesterol-clearing receptor. The woman's LDL cholesterol dropped from 448 milligrams per deciliter (mg/dl) -a concentration measured before gene therapy but while receiving a cholesterollowering drug - to 366 mg/dl.

This reading is about three times higher than it should be. Gene therapy also seemed to enhance the patient's response to 1ovastatin, a drug that works in part by spurring clearance of LDL.

The woman's cholesterol concentrations still put her at risk of a heart attack, Wilson cautions. Yet his team hopes that the experimental therapy will slow the dangerous deposition of plaque and thus buy this patient time. Indeed, X rays of the patient's coronary arteries indicate that her atherosclerosis has not progressed since the procedure.

The team has treated four other patients with this disorder. The researchers have yet to release data on any lipid benefits for those patients.