The operation was a success, and the patient lived.The patient is a 30-year-old French-Canadian woman, who has spentall of her life on genetic death row. She suffers from familialhypercholesterolemia (FH), a rare homozygotic gene defect thatprevents her body from flushing out surplus cholesterol.Burdened with the implacable buildup of this arterial plaque-formingsubstance, she suffered a heart attack at age 16 and underwent a triplecoronary bypass graft at 26. Two of her brothers died in their early 30sof the disease, which occurs when a victim receives copies of the lethalmutant gene from both parents.On June 5, 1992, this doomed FH patient underwent surgery to remove15 percent of her liver and transfect that organ's hepatocytes with thecorrect gene. This cDNA sequence encodes the receptor for low-density lipoprotein (LDL), which hustles unwanted cholesterol out ofthe body.Last Friday, nearly two years later, that one-shot gene therapy feat wasreported in Nature Genetics as "Successful ex vivo gene therapydirected to liver in a patient with familial hypercholesterolemia."Its principal author, gene therapist James Wilson, describes it as "thefirst report of human gene therapy in which stable correction of atherapeutic endpoint has been achieved." (Since the time of thesurgery, at the University of Michigan Medical Center, Wilson hasmoved to the University of Pennsylvania's Institute for Human GeneTherapy.)Wilson explained that "this represents the first example of stablecorrection of a therapeutic endpoint by gene therapy, in contrast toclinical trials that require repeated administration of short-lived targetcells such as lymphocytes for treatment of adenosine deaminasedeficiency." That was the genetic disorder corrected in the very firsttwo patients to undergo gene therapy of any kind -- the two little girlswith SCID (severe combined immunodeficiency disorders).At the time of her experimental surgery, that initial FH patient had aserum cholesterol reading of 545 mg/dl, vastly higher than currentnormal cutoff levels. Cholesterol-reducing drugs had failed to remedyher condition, and one of her three triple bypasses had failed.Michigan surgeon Steven Raper removed a 250-gram segment of herliver, which was rushed on ice to a tissue culture laboratory. There thehepatocytes were teased apart and seeded onto 800 Petri dishes. Thenretroviruses carrying normal copies of the missing human LDLreceptor gene were added to the cultures.Once tests confirmed that the hepatic cells had taken up the genes,they were returned to her body by way of the portal vein, whichdelivers blood to the liver.More medically predictive than cholesterol levels per se is the ratiobetween high- and low-density lipoproteins. Post-operatively, thepatient's LDL/HDL ratio declined beneficially from 10/13 before genetherapy to 5/8 after it. Another positive, though unexplained, resultwas that previously useless cholesterol-lowering medication started tohave an effect.As reported through an interpreter Friday in The New York Times, theFrench-speaking patient, now 22 months along since her gene therapy,said, "I feel very well physically and morally. I feel I can do morephysical activity, like skiing, dancing and other social activities."But Wilson tempers this rosy picture in his Nature Genetics report. "Itis unclear whether the partial correction of hypercholsterolemiaachieved in this patient will translate to improved clinical outcome. Itis encouraging ... that her coronary artery disease ...has not progressed... since the treatment," he said.Another slightly damp blanket came from the eminent Britishauthority, David Weatherall, honorary director of Oxford University'sInstitute of Molecular Medicine. In an editorial accompanying thepaper, he suggested a sort of placebo effect. "It is always possible thatthe patient was even more careful than usual with her diet, medicationand lifestyle."Weatherall also allowed that "despite all these ifs and buts, the work...represents a genuine step forward in the slow road to successfulsomatic gene therapy."Four more FH patients have already begun that journey. One is a 41-year-old woman, also from French Canada, where FH is six timesmore prevalent than the average. She underwent the liver-seedinggene therapy several months ago. Another is an 11-year-old girl whohad it last month.In his commentary, Weatherall also commented, "The clinical story ofthe first recipient of liver-directed ex vivo gene therapy, even forthose whose work takes them into daily contact with high-technologymedicine, rather hair-raising."

-- David N. Leff Science Editor

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