Atherosclerosis is a chronic inflammatory disease of the macrovasculature, leading to myocardial infraction as well as heart failure (HF). Oxidation of LDL (OxLDL) leads to its unregulated uptake by macrophages, causing foam cells, the initial lesion of atherosclerosis. OxLDL is also immunogenic, leading to the generation of autoantibodies to epitopes of OxLDL. We have cloned both murine and human monoclonal autoantibodies to OxLDL and shown that when they are radiolabelled and injected intravenously, they target atherosclerotic lesions and that some block the binding and uptake of OxLDL by macrophages. We propose to develop gene transfer techniques that would allow for the systematic expression from ectopic organs, such as liver of muscle, of such recombinant single chain antibodies (scFv) to OxLDL to affect the atherogenic process, for example by blocking OxLDL uptake by macrophages or by delivery to the lesion (which is rich in OxLDL) of important therapeutic molecules. The successful development of these techniques might provide novel therapeutic modalities to retard atherogenesis and improve contractility of the failing heart. There are increasing examples of beneficial effects in humans of the infection of monoclonal antibodies in a variety of different disease states. Therefore, these techniques may be of general utility and could be models by which constant and sufficient delivery of a recombinant antibody could be delivered extracellularly or intracellularly for a wide variety of therapeutic purposes.
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