Grant: Proof of Principle Program - Phase II

High levels of blood cholesterol are associated with serious cardiovascular complications including stiffening of the arteries and atherosclerosis, ultimately leading to heart attacks. Reduction of circulating levels of the bad cholesterol carrier, known as low density lipoprotein (LDL), is the best treatment to prevent long term cardiovascular disease and its associated complications. Since the early 1990s prescriptions of the oral drugs known as `statins` saved many lives and improved the health of millions of people. However, as much as 20% of the patients either do not respond to statins or are intolerant to this drug due to side effects. Accordingly, alternative drugs are needed for these patients and to further reduce LDL in many hypercholesterolemic individuals. The present invention describes a single domain antibody approach to block the function of the LDL regulating protein PCSK9 that we discovered in 2003. The project aims to validate the identified antibodies in model mice, as a prelude to pre-clinical studies.