Gene Knockout Rat Models for Cardiovascular, Diabetes and Atherosclerosis Research

12 Dec 2011
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Sigma-Aldrich® Corporation today announced that Sigma Advanced Genetic Engineering (SAGE™) Labs, an initiative of Sigma Life Science, has made available three genetically modified rat models that exhibit features key to studying conditions such as obesity, diabetes, atherosclerosis, high cholesterol, hypertension and familial hypercholesterolemia.

"Leptin, LDL receptor and ApoE gene knockout rats display phenotypes, physiology and metabolism sorely needed in studies of human cardiovascular diseases and diabetes, without requiring special, costly high-fat diets," explained Edward Weinstein, Director of SAGE Labs.

Leptin is a protein that regulates energy intake and expenditure. Loss of functional Leptin causes uncontrolled appetite, leading to severe obesity and abnormal metabolism. The Leptin knockout rats (KiloRat™) weigh almost double age-matched rats and have elevated serum cholesterol and triglyceride levels. The KiloRats also show signs of insulin resistance, a critical feature for diabetes research.

The low density lipoprotein (LDL) receptor knockout rats, which lack the receptor essential to preventing accumulation of LDL-cholesterol in the blood, have blood cholesterol levels 4-8 times higher than age-matched rats on low or high-fat diets. Elevated blood LDL is directly involved with the development of atherosclerosis, the process responsible for the majority of cardiovascular diseases.
 
Apolipoprotein E (ApoE) is a protein that is essential for normal processing of triglyceride-rich lipoprotein constituents. The disruption of ApoE, results in errant movement of lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system, and then into the blood. The ApoE knockout rats demonstrate a 4.5 fold increase in total serum cholesterol concentration at 10 weeks relative to the age-matched rats with normal diet. In addition to utility for studies of cardiovascular disease and diabetes, ApoE has recently been implicated in Alzheimer's disease, cognitive degeneration, immune system regulation and nerve injury repair.

Animal models with knockouts of LDL receptor or ApoE genes were previously available only in mice. "Rats are widely recognized as more indicative models of human cardiovascular disease, diabetes and atherosclerosis. A rat's heart rate is much closer to a human's and grows much larger, which enables more detailed physiological measurements and procedures, such as more frequent blood testing and insertion of stents," Weinstein explained. "And, critically, drug safety tests are performed in rats downstream. Using the same model organism from discovery to drug development enables much earlier and clearer answers to the key question: will this therapeutic translate into humans?"
Additional gene knockout rat models for cardiovascular disease and diabetes research are expected to be released in early 2012.

Scientists at SAGE Labs created the gene knockout rats through the SAGEspeed™ model creation process, which uses Sigma's CompoZr® Zinc Finger Nuclease (ZFN) technology to create sophisticated genetic modifications in rats, mice, rabbits, and other organisms CompoZr ZFN technology is the first to enable highly efficient, targeted editing of the genome of any species.

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