INTRACORONARY DELIVERY OF PLASMID DNA TO CARDIAC TISSUES

基因治疗有望在最基本的病理水平上成为治疗获得性和遗传性疾病的一项重大进展。具体来说，考虑到冠状动脉疾病是美国发病率和死亡率的主要原因，将基因转移到心脏的方法的发展是有吸引力的。尽管这种疾病的预防和治疗取得了进展，但仍有大量患者不是经皮或手术血运重建术的最佳候选人，通常是因为严重的远端血管疾病或先前失败的血运重建术。在这种情况下，冠状动脉侧枝的发育是缺血性心脏的重要适应性反应，但侧枝循环往往不足，尽管进行了最大的药物治疗，但仍会导致严重的心绞痛。治疗这些经常残疾的患者的新策略涉及局部递送血管细胞因子以诱导缺血心肌中的新血管生长（新血管生成）。人们很早就认识到基因治疗可以在新血管化方法中发挥重要作用。许多不同的基因转移方法已经在动物模型和一期人体临床试验中取得了不同程度的成功。需要进一步的工作来开发在心脏中表达血管生成转基因的方法。在第一阶段，将开发一种微创且临床可行的裸质粒DNA （pDNA）到心脏的体内递送系统。在II期，这些研究将通过测试pDNA递送hVEGF表达载体治疗猪慢性冠状动脉闭塞模型（ameroid constrictor）心脏缺血的临床益处来扩展。这些研究将为该疗法在III期的商业开发奠定基础。拟议的商业应用：SBIR提案将资助临床前研究，这些研究将构成人体临床试验和向FDA和NIH- RAC申请IND的基础。它的商业开发将通过启动临床试验（由Mirus赞助）和向大型制药和生物技术公司颁发许可证来完成，以便在未来三年内在其他医疗中心进行几项临床研究。

Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Specifically, the development of gene transfer methods into the heart is attractive given that coronary artery disease is the leading cause of morbidity and mortality in the United States. Despite advances in the prevention and treatment of this disorder there remains a large population of patients who are not optimal candidates for percutaneous or surgical revascularization, usually because of severe distal vessel disease or previous failed revascularization procedures. Coronary collateral development is an important adaptive response of the ischemic heart in this situation, but often the collateral circulation is inadequate and results in severe angina pectoris despite maximal medical therapy. A new strategy to treat these often disabled patients involves the local delivery of vascular cytokines to induce new blood vessel growth (neoangiogenesis) in the ischemic myocardium. It was recognized early on that gene therapy could play a major role in neovascularizarion approaches. Many different gene transfer methods have been tried with varying levels of success in animal models and phase I human clinical trials. Further work is required to develop the methods for expressing angiogenic transgenes in the heart. During Phase I, a minimally-invasive and clinically viable in Vivo delivery system of naked plasmid DNA (pDNA) to the heart will be developed. In Phase II, these studies will be extended by testing the clinical benefits of pDNA delivery of hVEGF expression vectors for treatment of cardiac ischemia in a pig chronic coronary occlusion model (ameroid constrictor). These studies will form the basis for the commercial development of this therapy during Phase III. PROPOSED COMMERCIAL APPLICATIONS: The SBIR proposal will fund pre-clinical studies that will form the basis for human clinical trials and an IND application to the FDA and NIH- RAC. Its commercial development will be accomplished by the initiation of clinical trials (sponsored by Mirus) and its licensing to larger pharmaceutical and biotechnology companies in order to have several clinical studies performed at other medical centers within the next three years.