GENE THERAPY WITH SOCS-3 IN INTIMAL HYPERPLASIA AND IN-STENT RESTENOSIS

SOCS-3 在内膜增生和支架内再狭窄中的基因治疗

• 批准号: 8247700
• 负责人: Devendra K. Agrawal
• 金额: $ 61.84万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247700
• 关键词: 5' Untranslated Regions; Angiography; Angioplasty; Apoptosis; Area; Arteries; Atherosclerosis; Attenuated; Balloon Angioplasty; Blood; Blood Platelets; Blood Vessels; Caliber; Cardiology; Cardiovascular system; Cell Proliferation; Cells; Cellular biology; Clinical; Coronary Angiography; Coronary Arteriosclerosis; Coronary artery; CpG Islands; Cytokine Inducible SH2-Containing Protein; Dependovirus; Development; Down-Regulation; Drug Controls; Endotoxic Shock; Epigenetic Process; Family suidae; Fibrinogen; Functional disorder; Gene Delivery; Gene Transfer; Genes; Goals; Growth; Growth Factor; Heart; Histology; Human; Hypermethylation; Hyperplasia; In Vitro; Induction of Apoptosis; Inflammatory; Injury; Insulin-Like Growth Factor I; Interferon Type II; Intervention; Investigation; Legal patent; Lesion; MAPK3 gene; Medial; Mediating; Metals; Methylation; Mitogens; Modeling; Molecular Biology; NF-kappa B; Pathogenesis; Pathology; Patients; Percutaneous Transluminal Coronary Angioplasty; Pharmaceutical Preparations; Phosphorylation; Positioning Attribute; Procedures; Promoter Regions; Proteins; Reaction; Research; Rheumatoid Arthritis; STAT3 gene; Scheme; Site; Smooth Muscle; Smooth Muscle Myocytes; Stenosis; Stents; Symptoms; TNF gene; Testing; Therapeutic; Thick; Thrombosis; Transgenes; Translating; Ulcer; Ultrasonography; Up-Regulation; Vascular Diseases; cytokine; gene therapy; in vivo; intima media; novel; overexpression; phase 1 study; prevent; promoter; public health relevance; response to injury; restenosis; restoration; transcription factor; tumor; vector control

DESCRIPTION (provided by applicant): Intimal hyperplasia and restenosis following interventional procedures remain significant clinical problems. Drug-eluting stents cause less intimal hyperplasia and less late luminal loss, but inhibit re- endothelialization of the stented segment making it more susceptible to thrombosis requiring longer periods of anti-platelet therapy. Clearly, an additional therapeutic approach would be useful to prevent intimal hyperplasia and provide long-term symptom-free control of coronary artery disease. SOCS3 regulates the activity of mitogens in VSMCs, and in the presence of both mitogen and inflammatory cytokines, the SOCS3 gene is silenced, leading to increased proliferative effect of growth factors. This justifies the introduction of the SOCS3 gene in coronary arteries as a viable approach to control intimal hyperplasia. The hypothesis is that delivery of the SOCS3 transgene locally to the site of angioplasty and stent injury prevents the development of neointimal hyperplasia and in-stent restenosis which is due to silencing of the SOCS3 gene by hypermethylation and enhanced STAT3 and NF-kB transcriptional activity in coronary artery smooth muscle cells. We propose to utilize hyperlipidemic and atherosclerotic microswine model with angioplasty and in-stent restenosis. Aim 1: Our hypothesis predicts that the introduction of SOCS3 transgene at the site of balloon angioplasty in atherosclerotic coronary artery will prevent the development of intimal hyperplasia. Aim 2: Our hypothesis predicts that the introduction of SOCS3 transgene at the site of bare metal stenting in atherosclerotic coronary artery will prevent in-stent restenosis and this would be superior to the effect of drug- eluting stent alone. In both these aims, AAV9-mediated gene transfer will be used to overexpress SOCS3 in VSMCs at the site of interventional procedure in coronary arteries of hyperlipidemic and atherosclerotic microswine. Clinical and histological parameters of intimal hyperplasia and in-stent restenosis in coronary arteries will be examined. Aim 3: Our hypothesis predicts that the intimal hyperplasia following balloon angioplasty and intravascular stenting is due to silencing of SOCS3 promoter by hypermethylation and enhanced transcriptional activity of STAT3 and NF-kB in coronary artery smooth muscle cells and that restoration of SOCS3 by gene therapy results in down-regulation of active NF-kB and STAT3, induction of apoptosis and growth suppression of VSMCs. We will determine whether or not aberrant hypermethylation of promoter regions in CpG islands is associated with transcriptional silencing of the SOCS3 gene and up- regulation of active NF-kB and STAT3 in SMCs of neointimal lesions in coronary artery following balloon angioplasty and with in-stent stenosis, whether or not this is suppressed by SOCS3 gene therapy. These studies will provide the conceptual support of our hypothesis and position us to translate our investigation into a clinical phase 1 study for the gene delivery of SOCS3 in patients with coronary artery disease. PUBLIC HEALTH RELEVANCE: Re-narrowing of coronary arteries in the heart after balloon angioplasty or placement of stents is serious problem. This is primarily due to uncontrolled growth of smooth muscle cells at the site of injury due to balloon angioplasty or the placement of stent in coronary artery. In this project we proposed to deliver a novel gene at the site of injury in the heart of atherosclerotic pig during these procedures to prevent the re-narrowing of the coronary arteries and keep them patent for longer period. The goal is to test the hypothesis that SOCS3 gene therapy is superior to drug-eluting stents. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical phase 1 study for the gene delivery in patients with coronary artery disease.

描述(由申请人提供)：介入手术后的内膜增生和再狭窄仍然是严重的临床问题。药物洗脱支架导致较少的内膜增生和较少的晚期管腔丢失，但抑制了支架部分的再内皮化，使其更容易发生血栓形成，需要更长时间的抗血小板治疗。显然，另一种治疗方法将有助于预防冠状动脉内膜增生，并提供长期无症状的冠状动脉疾病控制。SOCS3调节VSMC中有丝分裂原的活性，在有丝分裂原和炎性细胞因子存在的情况下，SOCS3基因被沉默，导致生长因子的增殖作用增强。这证明在冠状动脉中引入SOCS3基因是一种可行的控制内膜增生的方法。假设将SOCS3转基因基因局部输送到血管成形术和支架损伤部位，可防止新生内膜增生和支架内再狭窄的发展，这是由于冠状动脉平滑肌细胞中SOCS3基因高甲基化沉默和STAT3和NF-kB转录活性增强所致。我们建议利用高脂血症和动脉粥样硬化的小型猪模型进行血管成形术和支架内再狭窄。目的1：我们的假设是在动脉粥样硬化性冠状动脉球囊成形术的部位引入SOCS3转基因可以防止动脉内膜增生的发展。目的：我们的假设是在动脉粥样硬化性冠状动脉裸金属支架置入部位引入SOCS3基因可以预防支架内再狭窄，其效果优于单纯药物洗脱支架。在这两个目标中，AAV9介导的基因转移将被用来在高脂血症和动脉粥样硬化的小型猪冠状动脉介入手术部位的VSMCs中过表达SOCS3。将检查冠状动脉内膜增生和支架内再狭窄的临床和组织学参数。目的：我们的假说认为，血管球囊成形术和血管内支架置入术后的内膜增生是由于冠状动脉平滑肌细胞中SOCS3启动子的高甲基化以及STAT3和NF-kB转录活性的增强所致，而通过基因治疗恢复SOCS3可以下调活化的NF-kB和STAT3的表达，诱导VSMCs的凋亡和生长抑制。我们将确定CpG岛启动子区域的异常高甲基化是否与SOCS3基因转录沉默以及冠状动脉球囊成形术后新生内膜病变和支架内狭窄的SMC中活性的NF-kB和STAT3上调有关，无论这种情况是否被SOCS3基因治疗抑制。这些研究将为我们的假设提供概念性支持，并使我们能够将我们的研究转化为冠心病患者SOCS3基因传递的临床第一阶段研究。 公共卫生相关性：球囊血管成形术或支架置入后心脏冠状动脉再次狭窄是一个严重的问题。这主要是由于球囊血管成形术或冠状动脉支架置入术导致损伤部位的平滑肌细胞不受控制地生长所致。在这个项目中，我们建议在动脉粥样硬化猪的心脏损伤部位传递一个新的基因，以防止冠状动脉再狭窄并使其保持更长时间的通畅。目的是验证SOCS3基因治疗优于药物洗脱支架的假设。拟议的研究将为我们的假设提供概念性支持，并使我们能够将我们的研究转化为冠心病患者基因传递的临床第一阶段研究。