PTEN Gene Therapy for Vein Graft Disease

PTEN 基因治疗静脉移植疾病

• 批准号: 7846252
• 负责人: Christopher D Kontos
• 金额: $ 19.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846252
• 关键词: Adenovirus Vector; Adenoviruses; Animal Model; Arteries; Arteriovenous fistula; Autologous; Blood Vessels; Bypass; Canis familiaris; Capsid; Clinic; Clinical; Clinical Trials; Complex; Coronary; Coronary Arteriosclerosis; Coronary Artery Bypass; Data; Dependovirus; Developed Countries; Development; Disease; E2F transcription factors; Exposure to; Failure; Fistula; Gene Delivery; Growth; Harvest; Health Care Costs; Hemodialysis; Human; Hydrolysis; Hyperplasia; In Vitro; Incidence; Inflammation; Inflammatory Response; Investigational New Drug Application; Lead; Lipids; Mediating; Modeling; Morbidity - disease rate; Oligonucleotides; Outcome; PTEN gene; Patients; Peripheral; Peripheral arterial disease; Phase I Clinical Trials; Phase III Clinical Trials; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Prevention; Process; Recombinant adeno-associated virus (rAAV); Recombinants; Role; Saline; Saphenous Vein; Signal Pathway; Smooth Muscle Myocytes; Testing; Therapeutic; Therapeutic Agents; Transfection; Translating; Veins; Venous; adeno-associated viral vector; adenovirus mediated delivery; cell growth; clinically relevant; design; gene therapy; gene therapy clinical trial; graft failure; human FRAP1 protein; improved; mortality; novel strategies; overexpression; prevent; public health relevance; response; tool; transgene expression; vector; vector-induced

DESCRIPTION (provided by applicant): Atherosclerosis of coronary and peripheral arteries results in significant morbidity and mortality in the U.S. and other developed countries. Autologous saphenous veins are the most commonly used conduits for bypass grafting in both coronary and peripheral artery disease, and autologous veins are commonly employed for creation of arteriovenous fistulas (AVFs) for hemodialysis. The utility of these conduits is compromised by a high incidence of occlusive vein graft disease, yet no treatments exist to prevent this problem. Vein grafting provides an ideal opportunity for gene therapy, since veins are harvested from their native territory prior to grafting and can be treated ex vivo, thereby avoiding systemic exposure to the therapeutic agent. Recent Phase III clinical trials of an oligonucleotide decoy targeting the E2F transcription factor demonstrated no benefit for the prevention of vein graft failure in peripheral or coronary artery bypass grafting (CABG). Thus, there is a critical need for novel approaches to prevent vein graft failure. PTEN is a lipid phosphatase that antagonizes the effects of phosphoinositide (PI) 3-kinase, a central regulator of pathological vascular smooth muscle cell (VSMC) growth. We demonstrated previously that overexpression of PTEN in vitro inhibits the VSMC responses necessary for intimal hyperplasia. More importantly, adenovirus (Ad)-mediated delivery of PTEN to vein grafts ex vivo resulted in significant inhibition of intimal hyperplasia in a canine model of coronary artery bypass grafting (CABG). These findings suggest that PTEN gene therapy holds great promise for the prevention of clinical vein graft disease. However, adenoviral vectors induce transgene expression only on the order of weeks and are associated with a robust inflammatory response. Moreover, it is unknown whether the short-term expression achieved with AdPTEN will result in long-term vein graft patency. In contrast, newer adeno-associated virus (AAV) vectors achieve expression that is sustained for months to years and do not induce substantial inflammation. We hypothesize that long-term PTEN expression achieved with AAV will result in long-term vein graft patency rates comparable to or better than those obtained with AdPTEN. To test this hypothesis, the Specific Aims of this proposal are to: 1) Develop AAV-PTEN and optimize transduction of vascular smooth muscle cells and vein grafts; and 2) Compare 6-month aortocoronary saphenous vein graft (SVG) patency rates and intimal hyperplasia in dogs following ex vivo vein graft treatment with AdPTEN, AAV-PTEN, or saline control. Accomplishing these Specific Aims will determine the optimal agent for further clinical development, and this agent will be subsequently tested in clinical trials of human vein graft disease. PUBLIC HEALTH RELEVANCE: Autologous veins are commonly used as bypass conduits in patients with coronary and peripheral arterial disease and to create arterio-venous fistulas (AVFs) for hemodialysis, however these conduits have a high rate of failure due to intimal hyperplasia. PTEN gene therapy holds great promise to prevent vein graft failure, and studies in this proposal will determine the optimal approach for this therapeutic strategy. The results of these studies may have a substantial impact on outcomes for patients requiring venous bypass grafting and AVF placement.

描述（由申请人提供）：冠状动脉和外周动脉粥样硬化是美国和其他发达国家发病率和死亡率很高的疾病。自体隐静脉是冠状动脉和外周动脉疾病旁路移植术中最常用的导管，并且自体静脉通常用于血液透析中创建动静脉瘘（avf）。由于静脉移植物闭塞性疾病的高发，这些导管的效用受到了损害，但目前还没有治疗方法来预防这一问题。静脉移植为基因治疗提供了一个理想的机会，因为静脉在移植前从其原生区域采集，可以在体外治疗，从而避免全身暴露于治疗剂。最近针对E2F转录因子的寡核苷酸诱饵的III期临床试验表明，对外周或冠状动脉旁路移植术（CABG）中静脉移植失败的预防没有益处。因此，迫切需要新的方法来防止静脉移植失败。PTEN是一种脂质磷酸酶，可拮抗磷酸肌肽（PI） 3-激酶的作用，磷酸肌肽（PI） 3-激酶是病理性血管平滑肌细胞（VSMC）生长的中央调节剂。我们先前证明，PTEN在体外的过表达抑制内膜增生所必需的VSMC反应。更重要的是，腺病毒（Ad）介导的PTEN体外递送到静脉移植物中，在犬冠状动脉旁路移植术（CABG）模型中显著抑制了内膜增生。这些发现表明PTEN基因治疗在预防临床静脉移植疾病方面具有很大的前景。然而，腺病毒载体仅在数周内诱导转基因表达，并与强烈的炎症反应相关。此外，AdPTEN的短期表达是否会导致静脉移植物长期通畅尚不清楚。相比之下，较新的腺相关病毒（AAV）载体实现持续数月至数年的表达，并且不会引起实质性的炎症。我们假设AAV获得的长期PTEN表达将导致与AdPTEN获得的长期静脉移植通畅率相当或更好。为了验证这一假设，本课题的具体目标是：1)开发AAV-PTEN，优化血管平滑肌细胞和静脉移植物的转导；2)比较AdPTEN、AAV-PTEN和生理盐水对照体外静脉移植后6个月主动脉冠状动脉隐静脉移植（SVG）通畅率和内膜增生情况。完成这些特定目标将确定进一步临床开发的最佳药物，该药物将随后在人类静脉移植疾病的临床试验中进行测试。