The breeder of a mouse mutated to mimic humanatherosclerosis hails the new animal model as "a very powerfulmouse with extraordinary advantages."

Beverly J. Paigen, who heads atherosclerosis research at theJackson Laboratory in Bar Harbor, Maine, told BioWorld that "avery, very big market for screening drugs" awaits the rodent,which lacks a key gene that mediates removal of cholesteroland saturated fats from the body.

"When you're a pharmaceutical company," the mouse's denmother explained, "you can test in vivo for drugs to lowercholesterol levels, using either ordinary laboratory mice, byfeeding them diets astronomically high in cholesterol pluscholic acid to produce lesions, or the new apoE-minus mousewithout that diet."

Jackson Lab, a leading purveyor of research rodents, got itsfirst breeding pairs of the mice with the apoE gene knocked outfrom its creator, Nobuyo Maeda, a molecular geneticist at theUniversity of North Carolina. Late last month she introducedthe knockout mouse to a gene therapy meeting at Cold SpringHarbor Laboratory. Her paper, "SpontaneousHypercholesterolemia and Arterial Lesions in Mice LackingApolipoprotein E" appeared in Friday's issue of Science.

"Atherosclerotic cardiovascular disease is the major cause ofdeath in Western society," Maeda pointed out.

Apolipoprotein E (apoE), a glycoprotein, acts by binding withhigh affinity to receptors on chylomicron remnants -- dropletsthat engulf cholesterol -- as well as on low-density lipoproteins(LDLs), and hustling these atherogenic substances to wastedisposal via the liver. Maeda and her associates knocked apoEout of their mouse embryos by targeted gene disruption.

The resulting apoE-deficient mice had plasma cholesterol levelsfive times higher than their normal litter mates. By 3 monthsof age, fed on chow much lower in intake of fats and cholesterolthan the typical American diet, the mice had developed fattystreaks on their aortas. At 8 months (roughly equal to humanprime-of-life 30 years of age), the entry of their aortas tocoronary arteries was nearly blocked with fibrous plaques --the hallmark of myocardial infarction.

Hereditary apoE deficiency is rare in humans; only threeextended families with the homozygous mutation have beenfound. Ernst J. Schaefer and his colleagues at NIH described thefirst such kindred in 1981. Schaefer, who now directs the LipidClinic at Tufts University School of Medicine, finds Maeda'sapoE-minus model "nice and interesting, consistent with thehuman apoE deficiency," which he helped discover.

"How the model will be used in drug studies remains to beseen," Schaefer told BioWorld. "We already have a goodhamster model, closer to human physiology, and probablycheaper."

Paigen demurs that hamsters are more expensive than mice,less well-characterized and less amenable to geneticmanipulation.

Atherosclerosis is a disease of many root causes, still littleunderstood. Maeda's knockout mouse is slated for a starringpart in teasing out the role of apoE. She and Peigen are nowcrossbreeding the mutant with standard strains of mouse, andwith a model developed by Lawrence Berkeley Laboratory'sEdward Rubin, which overproduces the apoE gene product.

Thus, in Friday's issue of Cell, Michael S. Brown and Joseph L.Goldstein, who shared a Nobel prize in 1985 for elucidatingcholesterol metabolism in the body, wrote: "By crossbreedingwith the apoE mutant mice, at last the full power of mousegenetics will be available to unravel a multifactorial disease."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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