Novel anti-MCP-1 gene therapy against restenosis and atherosclerosis

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Because restenosis hampers clinical benefits of coronary intervention, prevention of restenosis is a major clinical challenge, which highlights the need of new therapeutic options such as gene therapy. Inflammatory responses to injury, which accelerate the recruitment and activation of monocytes through the activation of chemokines including monocyte chemoattractant protein-1 (MCP-1), may be the central part in restenosis and atherosclerosis. Thus, MCP-1 might be a novel therapeutic target against restenosis and atherogenesis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks the N-terminal amino acid 2 to 8, called 7ND, and works as a dominant-negative inhibitor of MCP-1. We have demonstrate that 1) MCP-1 is increased in restenotic and atherosclerotic lesions, 2) blockade of MCP-1 by this strategy suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) in the carotid artery of animals after balloon injury or stent placement, and 3) blockade of MCP-1 limited progression of pre-existing atherosclerotic lesions and improved the lesion composition into a more stable phenotype (containing fewer macrophages and lymphocytes, less lipid, more smooth muscle cells and collagen) in hypercholesterolemic mice. Therefore, vascular inflammation mediated by MCP-1-mediated monocyte infiltration and activation plays a central role in the development of restenotic changes in animals. Because this strategy appears to be a useful form of gene therapy against human restenosis, we are now on the way to perform this anti-MCP-1 gene therapy against patients undergoing percutaneous coronary intervention to reduce restenosis and its complications.