PTEN Gene Therapy for Vein Graft Disease

PTEN 基因治疗静脉移植疾病

• 批准号: 7634945
• 负责人: Christopher D Kontos
• 金额: $ 23.4万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634945
• 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; Developing 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的动脉粥样硬化导致美国和其他发达国家的显着发病率和死亡率。自体大隐静脉是冠状动脉和外周动脉疾病中最常用的旁路移植导管，并且自体静脉通常用于建立用于血液透析的动静脉瘘（AVF）。这些导管的实用性因闭塞性静脉移植疾病的高发生率而受到影响，但尚无治疗方法可以预防该问题。静脉移植为基因治疗提供了理想的机会，因为静脉是在移植前从其原生区域采集的，并且可以进行离体治疗，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，对于预防外周动脉或冠状动脉旁路移植术 (CABG) 中的静脉移植失败没有任何益处。因此，迫切需要新的方法来预防静脉移植失败。 PTEN 是一种脂质磷酸酶，可拮抗磷酸肌醇 (PI) 3-激酶的作用，而磷酸肌醇 (PI) 3-激酶是病理性血管平滑肌细胞 (VSMC) 生长的主要调节因子。我们之前证明，PTEN 体外过度表达会抑制内膜增生所需的 VSMC 反应。更重要的是，在犬冠状动脉旁路移植术（CABG）模型中，腺病毒（Ad）介导的PTEN体外递送至静脉移植物可显着抑制内膜增生。这些发现表明 PTEN 基因治疗对于预防临床静脉移植疾病具有巨大的前景。然而，腺病毒载体只能在几周的时间内诱导转基因表达，并且与强烈的炎症反应相关。此外，尚不清楚 AdPTEN 实现的短期表达是否会导致静脉移植物长期通畅。相比之下，较新的腺相关病毒（AAV）载体可实现持续数月至数年的表达，并且不会引起明显的炎症。我们假设用 AAV 实现的长期 PTEN 表达将导致长期静脉移植物通畅率与用 AdPTEN 获得的结果相当或更好。为了检验这一假设，本提案的具体目标是： 1）开发 AAV-PTEN 并优化血管平滑肌细胞和静脉移植物的转导； 2) 比较用 AdPTEN、AAV-PTEN 或盐水对照进行离体静脉移植治疗后狗的 6 个月主动脉冠状动脉隐静脉移植物 (SVG) 通畅率和内膜增生。实现这些具体目标将确定进一步临床开发的最佳药物，该药物随后将在人静脉移植疾病的临床试验中进行测试。 公众健康相关性：自体静脉通常用作冠状动脉和外周动脉疾病患者的旁路导管，并用于建立动静脉瘘（AVF）进行血液透析，但由于内膜增生，这些导管的失败率很高。 PTEN 基因疗法在预防静脉移植失败方面具有巨大前景，本提案中的研究将确定该治疗策略的最佳方法。这些研究的结果可能对需要静脉旁路移植和 AVF 放置的患者的预后产生重大影响。