ADENOVIRUS MEDIATED VEGF121 CDNA MYOCARDIAL ANGIONGENESI

血管成形术支架和冠状动脉旁路移植术仍然是治疗冠状动脉疾病CAD的主要介入治疗方法，但这些治疗方法仍然受到疾病复发、显著相关发病率和死亡率以及这些“机械”技术治疗弥漫性和小血管疾病的失败的限制。血管生成的基因治疗描述了另一种血管再生策略，即血管生成基因被递送到缺血组织以诱导新生血管。为了避免在先前的临床试验中使用患者作为自身对照的局限性，我们设计了一项前瞻性安慰剂对照、盲法、随机I/II期试验，以检验腺病毒（Ad）载体介导的人血管内皮生长因子121 cDNA （Ad/CU/VEGF121.1）心肌移植与生理盐水注射的结果。作为“非体外循环”冠状动脉旁路移植术（OPCAB）患者左前降支+/-右冠状动脉的辅助手段。将Ad/CU/VEGF121.1载体（10/9颗粒单位，30,1001等分或生理盐水）施用于旋流分布。潜在的假设是，直接给药于心肌的Ad/CU/VEGF121.1是安全的，可以改善心脏灌注和功能。这项随机、盲法、安慰剂对照的研究设计中，血管生成基因治疗以一致的方式进行，并通过运动测试、sestamibi SPECT扫描和MRI进行评估，没有体外循环诱导的潜在毒性，应该允许对两个特定假设进行评估：(1)以这种方式给药Ad/CU/VEGF121.1载体没有不良反应；(2)与Ad/CU/VEGF121.1治疗相关的心脏灌注和功能的整体和/或局部改善。由于研究设计是前瞻性的，安慰剂对照，盲法和随机的，结果应该有助于确定是否有必要进行更大规模的试验。

Angioplasty-stents and coronary artery bypass grafting remain the primary interventional therapies for the treatment of coronary artery disease CAD, but these treatments remain limited by recurrent disease, significant associated morbidities and mortality, and the failure of these "mechanical" techniques to treat diffuse and small vessel disease. Gene therapy for angiogenesis describes an alternative revascularization strategy whereby angiogenic genes are delivered to ischemic tissues for the purpose for inducing neovascularization. To avoid the limitations of patients acting as their own controls used in previous clinical trials examining this therapy for the treatment of CAD, we designed a prospective placebo controlled, blinded, randomized phase I/II trial to examine the consequence of adenovirus (Ad) vector-mediated myocardial transfer of the human vascular endothelial growth factor 121 cDNA (Ad/CU/VEGF121.1), as compared to saline injection, as an adjunct in individuals undergoing "off-pump" coronary artery bypass (OPCAB) grafting to the left anterior descending +/- the right coronary artery. The Ad/CU/VEGF121.1 vector (10/9 particle units in 30, 100 1 aliquots_ or saline will be administered to the circumflex distribution. The underlying hypothesis is that direct administration to the myocardium of Ad/CU/VEGF121.1 is safe and improves cardiac perfusion and function. This randomized, blinded, placebo controlled study design, in which angiogenic gene therapy is delivered in a consistent fashion and assessed by exercise testing, sestamibi SPECT scanning, and MRI without the potential toxicity induced by cardiopulmonary bypass, should allow the assessments of the two specific hypotheses: (1) there are no adverse effects in administering the Ad/CU/VEGF121.1 vector in this fashion: and (2) there are global and/or regional improvements in cardiac perfusion and function associated with Ad/CU/VEGF121.1 therapy. Because the study design is prospective, placebo controlled, blinded and randomized, the results should help determine whether larger trials of this therapy are warranted.