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

Abstract

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 mg and one control group), using the Infiltrator s 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 11.6972.78%, 2 mg 23.8172.81%, Po0.05 and 4 mg 23.3673.1%, Po0.05; n ¼ 12 per group) as well as the ratio of peripheral over aortic blood pressure (control 0.6470.03%, 2 mg 0.7570.02%, Po0.05 and 4 mg 0.7570.02%, Po0.05; n ¼ 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.

Repeated, but not single, VEGF gene transfer affords protection against ischemic muscle lesions in rabbits with hindlimb ischemia

“…In effect, the follow-up duration of most pre-clinical studies reporting benefits of gene therapy strategies on hindlimb ischemia has ranged from 1 week to 30 days. [22][23][24][25][26][27] Beneficial effects at longer follow-up times (up to 12 weeks) of AdVEGF 121 have been reported by Gowdak et al 28 in rats and rabbits with hindlimb ischemia. However, their results are not strictly comparable with ours because the gene was injected between 2 and 4 weeks before the induction of hindlimb ischemia.…”

In Vivo Human MCP-1 Transfection in Porcine Arteries by Intravascular Electroporation

“…Through this approach, a short surgical intervention would suffice, potentially reducing the risk for complication and increasing compliance of the patient. We have shown that gene transfer of the MCP-1 plasmid using a lipoplex vector system induced an increase in arterial conductance comparable to that observed after protein infusion (24). However, to reduce the complexity of the gene transfer system to the delivery of uncomplexed DNA while maintaining high and consistent expression levels, we investigated alternative methodologies.…”

Coronary collaterals—insights in molecular determinants and prognostic relevance

“…Experimental strategies include local growth-factor therapy [36], gene-transfer therapies [37] and cell therapy [38]. These are now widely seen as promising options for patients in which angioplasty and bypass surgery are not feasible due to especially severe disease and high complication risk.…”