Adjunct gene therapy for coronary artery bypass surgery

冠状动脉疾病冠状动脉疾病(CAD)是指为心肌提供血液的动脉(冠状动脉)由于其内壁上积聚了一种称为斑块的物质而变得硬化和狭窄，这一过程称为动脉粥样硬化。随着斑块的增大，冠状动脉内部变窄，流经其中的血液减少，心肌缺乏所需的氧气。这可能会导致心绞痛、胸痛或不适，最终患者可能会心脏病发作。如果心肌细胞没有获得足够的富氧血液，它们就会开始死亡，从而对心肌造成永久性损害。在美国和欧洲，冠心病是最常见的心脏病类型，也是导致男性和女性死亡的主要原因。冠心病的治疗一系列药物结合生活方式的改变最初用于治疗冠心病。然而，如果症状继续恶化，那么血管成形术或搭桥手术的直接干预可能是必要的。血管成形术包括充气动脉内的一个小气球，并将其拉出以移除阻塞，打开狭窄的冠状动脉。然后，可以在动脉中放置一种名为支架的装置，以在手术后保持动脉的打开。或者，在心脏两条或两条以上动脉被阻塞的情况下，可能需要进行冠状动脉旁路移植(CABG)手术。在这个手术中，来自身体其他部位的动脉或静脉，如来自腿部的隐静脉，被用来绕过狭窄的冠状动脉，改善流向心脏的血液，缓解胸痛，并可能防止心脏病发作。CABG手术中移植静脉的失败是非常有效的，但长期失败率很高。静脉移植失败的原因是手术中对静脉的操纵以及静脉暴露在心脏的高血压之下。手术后，静脉经历一个修复过程，导致静脉壁增厚。为了使移植物能在心脏的高血压中存活下来，需要一些增厚。然而，有时这种增厚是过度的，可能会导致动脉粥样硬化加速和限制通过静脉移植物的血流。对于静脉移植失败，目前还没有有效的治疗方法，唯一的选择是重复CABG，这是一个更危险的第二次过程。目的和目的我们的目标是开发基于基因的静脉移植物治疗方法，在静脉插入心脏之前，将其应用于体外静脉。为了实现这一目标，我们开发了一种高效的合成基因载体配方，基于基因、小片段蛋白质(肽)、脂质体的组合，脂质体是帮助将材料输送到细胞内的脂肪球。这种名为脂肽的制剂在将基因插入血管壁方面非常有效，已经在兔子身上证明了治疗效果。手术前将基因转移到静脉移植物中，一个月后发现静脉移植物增厚不到未处理对照组的一半。我们现在的目标是在大型动物模型猪身上进一步开发这项技术，这是一个更好的人类可能疗效的指标。这项研究还将开发测试和实验，以在临床试验之前评估该治疗的安全性。应用和益处每年进行的CABG手术超过一百万例。不幸的是，尽管手术非常有效，但长期移植物失败率很高，15%-20%的静脉移植物在一年内失败，50%的静脉移植物在10年内失败，导致进一步的严重并发症。一种提高静脉移植物存活率的有效治疗方法可能会影响数百万患者的生活。然后，同样的技术可以应用于其他带有基因的疾病的治疗，包括癌症。

Coronary Artery Disease Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle (the coronary arteries) become hardened and narrowed due to buildup of a material called plaque on their inner walls in a process known as atherosclerosis. As the plaque increases in size, the insides of the coronary arteries get narrower and less blood can flow through them, and the heart muscle is starved of the oxygen it needs. This can result in angina, chest pain or discomfort and eventually the patient may suffer a heart attack. Cells in the heart muscle begin to die if they do not receive enough oxygen-rich blood causing permanent damage to the heart muscle. CAD is the most common type of heart disease and the leading cause of death in the United States and Europe for both men and women. Treatment For CAD A range of medicines combined with lifestyle changes are used to treat CAD initially. However, if the symptoms continue to worsen, then direct intervention by angioplasty or bypass surgery may be necessary. Angioplasty involves inflating a small balloon within the artery and pulling it through to remove the blockage, opening the narrowed coronary arteries. A device called a stent may then be placed in the artery to keep it propped open after the procedure. Alternatively, in cases where two or more arteries in the heart are blocked, coronary artery bypass graft (CABG) surgery may be necessary. In this procedure arteries or veins from other areas of the body, such as the saphenous vein from the leg, are used to bypass the narrowed coronary arteries, improving blood flow to the heart, relieving chest pain, and possibly preventing a heart attack. Vein Graft Failure in CABG CABG surgery is very effective but there is a high rate of longer-term failure. Vein grafts failure is caused by the manipulation of the vein during surgery and the exposure of the vein to the high blood pressure in the heart. After surgery the vein undergoes a repair process, which leads to a thickening of the wall of the vein. Some thickening is desirable to enable the graft to survive the high blood pressure in the heart. However, sometimes this thickening is excessive and can lead to accelerated atherosclerosis and restricted blood flow through the vein graft. There is no effective therapy available for vein graft failure and the only option is to repeat the CABG, which is a more hazardous process second time. Aims and Objectives We aim to develop gene-based treatment for vein grafts, which will be applied to the vein when it is outside the body, prior to insertion into the heart. To achieve that goal we have developed an efficient synthetic gene carrier formulation, based on a combination of genes, small pieces of protein (peptides), liposomes, which are fatty spheres that help deliver materials into cells. The formulation, called Liptide , is very efficient at inserting genes into the walls of blood vessels and has already demonstrated therapeutic efficacy in rabbits. Genes were delivered into vein grafts before surgery and one month later it was shown that vein graft thickening was less than half that of untreated controls. We now aim to develop this technology further in a large animal model, the pig, which is a better indicator of likely efficacy in man. This study will also develop tests and experiments for evaluating the safety of the treatment prior to clinical trials. Applications and Benefits Each year more than a million CABG procedures are performed. Unfortunately, although surgery is very effective, there is a high rate of longer-term graft failure with 15-20% of vein grafts failing within one year and 50% at 10 years, leading to further serious complications. An effective treatment to promote the survival of vein grafts could affect the lives of millions of patients. The same technology could then be applied to the treatment of other diseases with genes, including cancers.