Share
Blog
Cite
Print
Email
BookmarkScienceDaily (Feb. 11, 2000) — DALLAS, Feb. 11 -- A new gene therapy tested in mice all but eliminated the fatty plaque deposits that can build up in arteries and cause heart attacks and strokes, according to a study in the February issue of Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association. Researchers transplanted a gene for the human version of apolipoprotein E (apoE) into a strain of mice bred specifically for the experiment. ApoE is a key protein involved in transporting and clearing cholesterol from the body. The animals getting the apoE gene had significant reductions in total cholesterol and triglycerides, an increased level of beneficial high-density lipoprotein (HDL) cholesterol, and complete regression of the fatty plaque blockages.
"There were tremendous differences in the number of fatty deposits between our treated and untreated animals, and we can say there were almost zero of the fatty deposits in the blood vessels of the gene therapy group," says senior author Nicolas Duverger, Ph.D., of Gencell in Vitry/Seine, France, a division of the pharmaceutical company Rhone-Poulenc Rorer. "Our first thought was to see if we could stop plaque development. But in fact, we observed complete regression of the lesions," he says.
The research was conducted in collaboration with scientists at the Pasteur Institute in Paris and Lille, France.
"There is a medical need for effective new therapies to treat people with high cholesterol levels," Duverger says. Eventually scientists may devise an apoE gene therapy to protect against heart disease that can be administered by injection every couple of years.
The most stunning finding occurred at about 200 days after treatment -- plaques in the gene-injected mice had essentially disappeared. "It has never been demonstrated that we could completely remove plaque in an animal or human just by altering the lipoprotein contents of the blood by a gene," Duverger says.
The researchers bred a strain of mice that had very high cholesterol levels and deficient immune systems. One group of mice received the apoE gene therapy and a second group did not.
Total cholesterol levels sank rapidly in the treated mice, dropping from a whopping level of 591 milligrams per deciliter down to just 92 mg/dL in three weeks time.
The beneficial changes in the blood cholesterol levels of the treated mice became evident on day four of the experiment. The changes persisted for at least five months in the mice getting the higher dose of the apoE gene, and then a rise in cholesterol began. Mice injected with a lower dose of the gene had a similar drop in cholesterol levels, however their levels started to rise sooner than the mice who received higher doses of the gene therapy. Researchers say it signals that the amount of improvement in cholesterol levels was dependent on the size of the dose of gene therapy.
Treated mice also had a sharp increase in HDL "good" cholesterol, which clears fat from the body, and a drop in their levels of "bad" LDL cholesterol, compared to the untreated mice. The treated mice also experienced drops in their levels of triglycerides.
ApoE sits on the surface of fat particles that circulate in the blood, including cholesterol and triglycerides. It binds to cells in the liver, which can then rid the body of the fats. High blood cholesterol is a major risk factor for coronary heart disease.
"The apoE gene binds with the particles of LDL cholesterol and triglycerides and carries them out of the body," Duverger says. However, he adds that the increased levels of HDL cholesterol are harder to explain. "It may be due to apoE binding to the HDL particles and helping to remove the plaques."
###
Co-authors are Caroline Desurmont, Ph.D.; Jean-Michel Caillaud, M.D.; Florence Emmanuel, M.D.; Patrick Benoit, M.D.; Jean Charles Fruchart, M.D.; Graciela Castro, M.D.; Didier Branellec, M.D.; and Jean-Michel Heard, M.D.
Story Source:
Adapted from materials provided by American Heart Association.
Note: If the story's author is not given, the name of the story's source is used instead.
