University of California

Ionis Pharmaceuticals, Inc.

Aldons J Lusis

Richard Theodore Lee

Margarete Mehrabian

Brian Parks

Hooman Allayee

Provided herein are methods, compounds, and compositions for reducing expression of an AGPAT5 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids, insulin resistance and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a cardiometabolic disease, disorder or condition, or a physiological marker thereof, in an individual in need.

Modulation of AGPAT5 expression

5-LO is expressed in the monocyte/macrophages (mono/mac) and foam cells of atherosclerotic lesions and is differentially expressed in CAST and CON6 mice relative to B6 mice. Mice heterozygous for a null mutation of 5-LO, when placed on an LDLR&#x2212;/&#x2212; background, have dramatically reduced atherosclerosis as compared to control LDLRmice. In a genetic epidemiologic study, it is found that a common 5-LO polymorphism is strongly associated with carotid artery intima-media thickness (IMT) and coronary artery disease patients. These results indicate that 5-LO and the leukotriene biosynthetic pathway is a major contributor to atherogenesis in animal models, and in atherosclerosis susceptibility in humans.

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Tarzana, CA, United States of America

Aldons J Lusis