Local Delivery of Anti-Monocyte Chemoattractant Protein-1 by Gene-Eluting Stents Attenuates In-Stent Stenosis in Rabbits and Monkeys

Abstract

Objective-We have previously shown that the intramuscular transfer of the anti-monocyte chemoattractant protein-1 (MCP-1) gene (called 7ND) is able to prevent experimental restenosis. The aim of this study was to determine the in vivo efficacy and safety of local delivery of 7ND gene via the gene-eluting stent in reducing in-stent neointima formation in rabbits and in cynomolgus monkeys. Methods and Results-We here found that in vitro, 7ND effectively inhibited the chemotaxis of mononuclear leukocytes and also inhibited the proliferation/migration of vascular smooth muscle cells. We then coated stents with a biocompatible polymer containing a plasmid bearing the 7ND gene, and deployed these stents in the iliac arteries of rabbits and monkeys. 7ND gene-eluting stents attenuated stent-associated monocyte infiltration and neointima formation after one month in rabbits, and showed long-term inhibitory effects on neointima formation when assessments were carried out at 1, 3, and 6 months in monkeys. Key Words: restenosis Ⅲ inflammation Ⅲ leukocytes Ⅲ stents Ⅲ smooth muscle cells T he use of polymer-coated drug-eluting stents (DES) for local drug delivery has proved to be a useful strategy for the prevention of restenosis. 1-3 However, recent clinical reports raise the possibility of a risk of stent thrombosis in DES compared with bare metal stent. 4 -6 Drugs released from first-generation DES (sirolimus or paclitaxel) exert distinct biological effects 3,4 : although primarily aimed to prevent vascular smooth muscle cell (VSMC) proliferation, which is one of central factors in the pathogenesis of restenosis, they also impair reendothelialization, which leads to delayed arterial healing and thrombogenesis. The use of sirolimuseluting stents in a porcine model was associated with no apparent long-term effects and with the delayed inflammation and proliferation. 7,8 In human pathologic study with 40 patients who died after the currently-approved DES implantation, it was suggested that the DES caused a persistent fibrin deposition and delayed reendothelialization compared with bare metal stent implantation. 9 Therefore, the development of a novel DES system with less adverse effects is needed. Conclusions-StrategyWe have recently devised a new gene therapy strategy for the delivery of the anti-monocyte chemoattractant protein-1 (MCP-1) in which plasmid cDNA encoding a mutant MCP-1 gene is transfected into skeletal muscle. 10 This mutant MCP-1 protein, called 7ND, lacks the N-terminal amino acids 2 through 8 and has been shown to function as a dominantnegative inhibitor of MCP-1. Using this systemic gene transfer strategy, we have demonstrated that blocking MCP-1-derived signals reduced neointima formation after balloonand stent-induced injury 11-14 and atherosclerosis 15,16 in animals, including nonhuman primates. Overall, these data suggest that an antiinflammatory strategy targeting MCP-1 may be an appropriate and reasonable approach for the prevention of restenosis.Local delivery of 7ND through a gene-eluting stent ma...

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

“…We previously reported the central role of monocyte-mediated inflammation in the pathogenesis of instent neointima formation [28][29][30][31] and the formulation of polymeric gene-eluting stents or nuclear factor kappa-B decoy, inhibiting in-stent stenosis 28,32) ; however, although advanced polymer technology was used, we were not able to formulate appropriate statin coating on metallic stents (authors' unpublished observation). An important finding of this study is that pitavastatin-NP-eluting stents attenuated in-stent stenosis (neointima formation) as effectively as sirolimus-eluting sue factor expression ( Fig.…”

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

“…We and others have reported that monocytemediated inflammation induced by monocyte chemoattractant protein-1 (MCP-1) plays a central role in the pathogenesis of neointima formation 24,[32][33][34][35][36] and in atherogenesis 37,38) . If imatinib and anti-MCP treatment exert their effects through different pathways, it would be interesting to examine whether combined In conclusion, blockade of PDGF signaling by imatinib-NP inhibited the proliferation of VSMC with no adverse effects on endothelial cells in vitro, and an imatinib-NP-eluting stent attenuated in-stent neointimal formation in porcine coronary arteries in vivo.…”

Achievements and Prospects in the Field of Gene-Eluting Coronary Stents

“…В соответствии с этим терапевтическим под-ходом Egashira и коллеги [21] оценили эффектив-ность стентов с плазмидной ДНК, кодирующей доминантный негативный вариант MCP-1. Стен-ты, развернутые в подвздошных артериях кроли-ков и макак с гиперхолестеринемией, приводили к снижению инфильтрации макрофагов примерно на 20 % в месте имплантации стента и ослаблению рестеноза на 20-30 % по сравнению с НМС [36].…”