Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries

Abstract

Background-Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries. Methods and Results-Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using ␤-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3-coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with ␤-galactosidase-expressing adenovirus (RAdlacZ

Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation

“…Indeed, approaches that target the inhibition of VSMC proliferation have been found to be more promising in arresting the development of neointima. [11][12][13][14] Toward elucidation of signal transduction mechanisms that are ubiquitously involved in the mitogenic actions of various VSMC agonists, we have shown previously that both receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) agonists such as platelet-derived growth factor-BB (PDGF-BB) and thrombin, respectively, activate nuclear factor of activated T cells (NFATs) and signal transducer and activator of transcription-3 (STAT-3) in stimulating VSMC growth and/or motility. 9,[15][16][17][18] Early studies from various laboratories have shown that STATs play an important role in the regulation of cytokineinduced gene expression.…”

Gene therapy for in-stent restenosis: Targets and delivery system

“…The potency of TIMP-1 as a therapeutic gene for antineointimal hyperplasia has been verified in various animal models (47,48). Johnson et al (48) found that stent-based delivery of TIMP-3 adenovirus inhibits neointimal formation in porcine coronary arteries (48). Downregulation of platelet-derived growth factor-β receptor expression and upregulation of plasminogen activator inhibitor-1 and light-type caldesmon, a potent cytostatic and antiangiogenic protein, using a gene targeting and adenoviral gene transfer approach, has also been found to inhibit neointima formation (49).…”

“…Although early studies using marimastat, a broad-spectrum MMP inhibitor, showed significantly reduced neointimal formation in cultured human saphenous vein graft segments, the potential of marimastat as an antimetastatic agent was halted at phase III due to a lack of efficacy and dose-limiting toxicity (46). The potency of TIMP-1 as a therapeutic gene for antineointimal hyperplasia has been verified in various animal models (47,48). Johnson et al (48) found that stent-based delivery of TIMP-3 adenovirus inhibits neointimal formation in porcine coronary arteries (48).…”

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

“…Следовательно, стабилизация внеклеточного ма-трикса может служить ограничением миграции ГМК к неоинтиме. В соответствии с этой идеей Johnson и его коллеги [30] полностью иммоби-лизировали суспензию Ad-вектора, кодирующего синтез тканевого ингибитора металлопротеина-зы-3 (TIMP3), на стенты из нержавеющей стали с полифосфорилхолиновым покрытием. На 28-е сутки после имплантации стента в сонные арте-рии свиньи объем неоинтимы был уменьшен на 40 и 50 % у животных с Ad-TIMP3-выделяющими стентами по сравнению со свиньями, которым были установлены НМС [30].…”