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

基本信息

批准号：
8452694
负责人：
Devendra K. Agrawal
金额：
$ 58.7万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8452694
关键词：
5&apos 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

项目摘要

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.

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重要的临床问题。药物洗脱支架引起较少的内膜增生和较少的晚期管腔损失，但抑制支架段的再内皮化，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，额外的治疗方法将有助于预防内膜增生并提供冠状动脉疾病的长期无症状控制。 SOCS3 调节 VSMC 中丝裂原的活性，在丝裂原和炎症细胞因子同时存在的情况下，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 基因是控制内膜增生的可行方法。假设将 SOCS3 转基因局部递送至血管成形术和支架损伤部位，可防止新内膜增生和支架内再狭窄的发生，这是由于高甲基化导致 SOCS3 基因沉默以及 STAT3 和 NF-kB 转录活性增强所致。冠状动脉平滑肌细胞。我们建议利用高脂血症和动脉粥样硬化微型猪模型进行血管成形术和支架内再狭窄。目标 1：我们的假设预测，在动脉粥样硬化冠状动脉球囊血管成形术部位引入 SOCS3 转基因将阻止内膜增生的发展。目标2：我们的假设预测，在动脉粥样硬化冠状动脉裸金属支架置入部位引入SOCS3转基因将预防支架内再狭窄，这将优于单独药物洗脱支架的效果。在这两个目标中，AAV9介导的基因转移将用于在高脂血症和动脉粥样硬化微型猪的冠状动脉介入手术部位的VSMC中过度表达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。目标 3：我们的假设预测，球囊血管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 启动子高甲基化沉默以及 STAT3 和 NF-kB 转录活性增强所致，并且基因治疗结果恢复了 SOCS3下调活性 NF-kB 和 STAT3、诱导细胞凋亡和抑制 VSMC 生长。我们将确定 CpG 岛启动子区域的异常高甲基化是否与球囊血管成形术和支架内冠状动脉新生内膜病变的 SMC 中 SOCS3 基因的转录沉默以及活性 NF-kB 和 STAT3 的上调有关狭窄，无论该现象是否被 SOCS3 基因治疗所抑制。这些研究将为我们的假设提供概念支持，并使我们能够将我们的研究转化为针对冠状动脉疾病患者的 SOCS3 基因递送的临床 1 期研究。