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的主要介入疗法，但这些治疗仍然受到疾病复发、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。用于血管生成的基因治疗描述了一种替代的血管重建策略，其中将血管生成基因递送到缺血组织以诱导新血管形成。为了避免以往临床试验中使用的患者作为其自身对照的局限性，我们设计了一项前瞻性安慰剂对照、盲法、随机I/II期试验，以检查腺病毒（Ad）载体介导的人血管内皮生长因子121 cDNA心肌转移的后果（Ad/CU/VEGF121.1），与盐水注射相比，在经历“非体外循环”冠状动脉旁路（OPCAB）移植到左前降支+/-右冠状动脉的个体中作为辅助。将Ad/CU/VEGF 121.1载体（30、100 μ l等分试样中的10/9颗粒单位）或盐水施用至回旋支分布。潜在的假设是，直接给予心肌的Ad/CU/VEGF 121.1是安全的，并改善心脏灌注和功能。这种随机、盲法、安慰剂对照的研究设计，其中血管生成基因治疗以一致的方式递送，并通过运动试验、sestamibi SPECT扫描和MRI评估，而没有心肺转流术诱导的潜在毒性，应该允许评估两个特定的假设：（1）以这种方式施用Ad/CU/VEGF 121.1载体没有副作用：和（2）与Ad/CU/VEGF 121.1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，安慰剂对照的，盲法和随机的，结果应该有助于确定是否有必要对这种疗法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.