Nonviral monocyte chemoattractant protein-1 gene transfer improves arteriogenesis after femoral artery occlusion

• Published in: Gene therapy Vol. 11; no. 23; pp. 1685 - 1693
• Main Authors: MUHS, A, LENTER, M. C, SEIDLER, R. W, ZWEIGERDT, R, KIRCHENGAST, M, WESER, R, RUEDIGER, M, GUTH, Brian
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2004
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Aorta; Applied cell therapy and gene therapy; Arterial Occlusive Diseases - metabolism; Arterial Occlusive Diseases - therapy; Biological and medical sciences; Biotechnology; Blood pressure; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Collateral Circulation - genetics; Conductance; Disease Models, Animal; Femoral artery; Femoral Artery - metabolism; Femur; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene transfer; Genetic Therapy - methods; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Liposomes; Medical sciences; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Occlusion; Peripheral Vascular Diseases - metabolism; Peripheral Vascular Diseases - therapy; Plasmids; Polymerase Chain Reaction - methods; Proteins; Swine; Swine, Miniature; Transfection; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transgenes; Veins & arteries; Germany; Monocyte; minipig; arteries; monocyte chemoattractant protein-1; nonviral gene transfer; Artery; Protein; Genetic transfer; Collateral circulation; Blood vessel; Circulatory system; Artery occlusion; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302360

Local infusion of recombinant monocyte chemoattractant protein-1 (MCP-1) has been shown to enhance collateral artery formation in rabbit and pig hindlimb models. Owing to clinical disadvantages of protein infusion, a nonviral, liposome-based MCP-1 gene transfer was developed. Collateralization in a porcine hindlimb model served to provide a proof-of-principle for the functional benefit of MCP-1 overexpression. Development of arterial conductance as a measure of functionally relevant collateralization was evaluated in occluded as well as untreated hindlimbs in each animal. At the time of occlusion, MCP-1 and control DNA/DC-30 lipoplexes were transferred to femoral arteries of Goettingen minipigs (two therapeutic MCP-1 groups: 2 and 4 microg and one control group), using the Infiltrator local drug-delivery device. At 2 weeks following occlusion, collateralization was determined as changes in peripheral haemodynamic conductance, peripheral over aortic blood pressure ratio and angiographically visible morphology of the peripheral vessel tree. Nonviral MCP-1 gene transfer significantly improved peripheral conductance (control 11.69+/-2.78%, 2 microg 23.81+/-2.81%, P<0.05 and 4 microg 23.36+/-3.1%, P<0.05; n=12 per group) as well as the ratio of peripheral over aortic blood pressure (control 0.64+/-0.03%, 2 microg 0.75+/-0.02%, P<0.05 and 4 mug 0.75+/-0.02%, P<0.05; n=12 per group) when compared to the untreated controls 2 weeks after occlusion. Thus, it could be demonstrated for the first time that in situ overexpression of MCP-1 following local nonviral gene transfer is a potential approach to improve peripheral collateralization.