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: 8627200
• 负责人: Devendra K. Agrawal
• 金额: $ 60.26万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627200
• 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.

描述（由申请人提供）：干预程序后的内膜增生和再狭窄仍然是重大的临床问题。药物洗脱支架会导致较少的内膜增生和较少的腔内损失，但抑制了支架段的再层层化，从而使其更容易受到血栓形成，需要更长的抗血域治疗。显然，另一种治疗方法将有助于预防内膜增生并提供对冠状动脉疾病的长期无症状控制。 SOCS3调节VSMC中有丝分裂的活性，在存在有丝分裂原和炎症细胞因子的情况下，SOCS3基因沉默，从而增加生长因子的增殖作用增加。这证明了在冠状动脉中引入SOCS3基因作为控制内膜增生的可行方法。假设是，SOCS3转基因局部向血管成形术和支架损伤部位的递送阻止了新的增生和内部再狭窄的发展，这是由于高甲基化和增强的STAT3和NF-KB转录活性在冠状动脉齐平滑体体光滑体现中对SOCS3基因的沉默。我们建议利用具有血管成形术和内部再狭窄的高脂症和动脉粥样硬化的微酮模型。 AIM 1：我们的假设预测，在动脉粥样硬化冠状动脉动脉动脉动脉动脉成形术的位点引入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中裸机支架位点的SOCS3转基因引入将预防内部再狭窄，这将优于单独使用药物支架的效果。在这两个目的中，AAV9介导的基因转移将用于在高脂症和动脉粥样硬化微酮的冠状动脉动脉中的VSMC中过表达SOCS3。将检查内膜增生和冠状动脉内狭窄的临床和组织学参数。目的3：我们的假设预测，气球血管成形术和血管内置定后的内膜增生是由于SECS3启动子通过高甲基化对SOCS3启动子的沉默和STAT3和NF-KB的转录活性增强所致抑制VSMC。我们将确定CPG岛中启动子区域的异常过度甲基化是否与SOCS3基因的转录沉默以及在冠状动脉成形术和不sttensis后被抑制的冠状动脉病变中的活性NF-KB和STAT3进行了调节，无论是在冠状动脉外形术后抑制还是不接受SICS3基因3 necte cene，这些研究将为我们的假设提供概念上的支持，并将我们的研究转化为冠状动脉疾病患者SOCS3基因递送的临床1期研究。

项目成果

Successful transfection of genes using AAV-2/9 vector in swine coronary and peripheral arteries.

使用 AAV-2/9 载体在猪冠状动脉和外周动脉中成功转染基因。

• DOI: 10.1016/j.jss.2011.02.032
• 发表时间: 2012-06-01
• 期刊: The Journal of surgical research
• 作者: Pankajakshan D;Makinde TO;Gaurav R;Del Core M;Hatzoudis G;Pipinos I;Agrawal DK
• 通讯作者: Agrawal DK

In vitro differentiation of bone marrow derived porcine mesenchymal stem cells to endothelial cells.

• DOI: 10.1002/term.1483
• 发表时间: 2013-11
• 期刊: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE
• 影响因子: 3.3
• 作者: Pankajakshan, Divya;Kansal, Vikash;Agrawal, Devendra K.
• 通讯作者: Agrawal, Devendra K.