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Gene transfer using mutant form of good cholesterol cuts vascular plaque and inflammation

e apo A-I gene and the apo E gene. Without these genes, they develop very high cholesterol levels and arterial plaque and are incapable of producing their own apo A-I.

"Any apo A-I that these mice have will come from our gene transfer, making the experimental design very clean," Shah noted.

The genes were transferred to the female mice during a bone marrow transplant from male mice. Because male DNA carries a y chromosome and female DNA does not, the gender mismatch enabled the researchers to precisely track the donor bone marrow.

To deliver the gene to the arterial wall, the researchers used a "signal molecule" when they put the genes into the bone marrow. The signal molecule selectively goes into immune system cells called macrophages, which go into the arterial wall.

"We examined the ability of both the wild type and the apo A-I Milano gene to move cholesterol out of the macrophages, a process called cholesterol efflux. This is one of the mechanisms by which HDL and apo A-I work to reduce plaque: They facilitate the removal of cholesterol from the macrophages in the plaque and deliver it to the liver for elimination," Shah said. "We used three methods in our experiment and all three methods demonstrated that macrophages containing the apo A-I Milano gene were more effective in effluxing cholesterol out of them, compared to those carrying the wild type apo A-I gene. Therefore, we concluded, the greater beneficial effect of A-I Milano gene transfer is most likely related to a greater efficiency of A-I Milano in promoting the removal of cholesterol from the macrophages."

Shah, who holds the Shapell and Webb Family Endowed Chair in Cardiology at Cedars-Sinai, has been studying apo A-I Milano in its various forms for about 13 years. He and his colleagues developed a synthetic version of the protein and conducted animal studies at Cedars-Sinai that led to human trials at the Cleveland Clinic in which intravenous injections w
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Source:Cedars-Sinai Medical Center


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