Cholesterol-Free Mice to Aid Drug Development

Researchers have developed a line of genetically engineered mice that are unable to synthesize cholesterol and instead use a different sterol, called desmosterol.

Investigators at Quark Biotech, Inc. (Ness Ziona, Israel) bred mice lacking the gene Dhcr24, which encodes the enzyme desmosterol reductase, the catalyst for the last stage of cholesterol synthesis, a process involving 20 steps and at least 19 enzymes.

It was possible to develop these mice because during gestation mice get their cholesterol from their mother, unlike humans, where the fetus must rely on its own production of cholesterol. The cholesterol-free mice were smaller than normal mice and are also infertile but otherwise relatively healthy. The physical condition of the mice was much better than had been expected, considering the severe defects that had been observed in the two patients suffering from demosterolosis caused by an autosomal recessive condition.

"We were surprised by the fact that a mouse lacking cholesterol can survive and develop into adulthood with little effect, when cholesterol accounts for approximately 99% of all steroids in mammals,” said senior author Dr. Elena Feinstein, vice-president for technology development at Quark Biotech. "We believe that this mouse can become a highly resourceful tool to further understand the role of cholesterol in the different organs. This knowledge can in the future help discover novel drugs and understand the mechanism of action of existing drugs for metabolic diseases and cancer, among others.”



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