Dec. 1 /PRNewswire/ -- Tularik Inc. (Nasdaq: TLRK - news) today announced the discovery of two genes responsible for a rare human genetic disorder. Tularik's researchers, working in collaboration with scientists from the University of Texas Southwestern Medical Center, have identified the genes that cause sitosterolemia. Patients with sitosterolemia have high cholesterol levels and typically develop life-threatening coronary artery disease. The discovery was published in the December 1 issue of Science.
The genes discovered encode two previously unknown protein molecules that are members of the class of ATP-binding cassette (ABC) transporter proteins. The newly discovered proteins, ABCG5 and ABCG8, latch onto cholesterol in the liver and small intestine. In the intestines, the proteins are responsible for blocking absorption of dietary cholesterol. In the liver, the proteins help excrete cholesterol into bile.
``While sitosterolemia is a rare disease, these findings represent a significant breakthrough for understanding the common forms of hypercholesterolemia. The genes we've discovered have very important functions. Essentially, they are gatekeepers of cholesterol absorption and secretion in the body,'' said David V. Goeddel, Ph.D., Tularik's Chief Executive Officer. ``Our research has opened a path to the development of novel small molecule therapeutics that may be of use to a wide patient population.''
In healthy individuals, cholesterol levels are maintained, in part, by the coordinate regulation of dietary cholesterol absorption in the intestine and excretion in the bile. Patients with sitosterolemia have excessive absorption and inadequate excretion into the bile, which results in dangerously high cholesterol levels. High cholesterol, in turn, can lead to plaque build-up in the arteries and coronary artery disease.
The Tularik team has succeeded in linking the disease to a molecular mechanism of action. ``In addition, we've shown that the two genes in question are regulated by transcription factors called liver X receptors (LXRs),'' said Bei Shan, Ph.D., Program Director of Lipid Disorders at Tularik. ``Tularik has identified several synthetic compounds that bind to LXRs, and we're now evaluating these compounds in various animal models of hypercholesterolemia,'' he added.
Tularik's work with ABC proteins and LXRs is part of a larger research agenda focused on several biochemical targets, all of which may be important in the regulation of cholesterol levels in patients.... |
