Mouse Models for Drug Discovery

Philip N. Howles Ph.D., Philip N. Howles

Gabriele Proetzel, Michael V. Wiles

Inhibitors of cholesterol absorption have been sought for decades as a means to treat and prevent cardiovascular diseases (CVDs) associated with hypercholesterolemia. Ezetimibe is the one clear success story in this regard, and other compounds with similar efficacy continue to be sought. In the last decade, the laboratory mouse, with all its genetic power, has become the premier experimental model for discovering the mechanisms underlying cholesterol absorption and has become a critical tool for preclinical testing of potential pharmaceutical entities. This chapter briefly reviews the history of cholesterol absorption research and the various gene candidates that have come under consideration as drug targets. The most common and versatile method of measuring cholesterol absorption is described in detail along with important considerations when interpreting results, and an alternative method is also presented. In recent years, reverse cholesterol transport (RCT) has become an area of intense new interest for drug discovery since this process is now considered another key to reducing CVD risk. The ultimate measure of RCT is sterol excretion and a detailed description is given for measuring neutral and acidic fecal sterols and interpreting the results.