Gene Therapy for Therapeutic Angiogenesis

描述(由申请人提供)： 虽然血管成形术和冠状动脉旁路移植术通常用于治疗冠心病，但许多患者并不适合这些手术。新的治疗方法，如“治疗性血管生成”，使用生长因子蛋白或基因来诱导缺血心肌的血运重建，可能提供所需的替代方案。在第一阶段的研究中，我们启动了血管重建基因疗法的发展。编码血管生成基因碱性成纤维细胞生长因子(FGF2)的载体被构建在胶原基质中，当输送到缺血心肌时，既能诱导新生血管，又能恢复心肌的收缩能力。我们现在建议通过先进的临床前研究继续这项工作，旨在使IND提交和启动I期临床安全性研究。具体目的#1建议在剂量递增疗效研究中评价胶原-明胶基质中的AdFGF2改善心肌收缩能力的能力。具体目标#2描述了用于临床前和临床研究的原装AdFGF2的开发、放大和cGMP制造。具体目标#3描述了评价AdFGF2在胶原-明胶中的急性毒理学和生物分布。产生的数据将建立在动物身上的全面疗效和安全性数据。

DESCRIPTION (provided by applicant): Although angioplasty and coronary bypass grafting are commonly used to treat coronary heart disease, many patients are not candidates for these procedures. New treatments, such as "therapeutic angiogenesis", in which growth factor proteins or genes are used to induce revascularization of ischemic myocardium, may provide the alternatives needed. In Phase I studies, we initiated development of gene therapy for revascularization. Vectors encoding the angiogenic gene basic fibroblast growth factor (FGF2) were formulated in collagen-based matrices, and when delivered to ischemic myocardium induced both neovascularization and restoration of myocardial contractility. We now propose to continue this work through advanced pre-clinical studies, designed to enable an IND submission and initiation of a Phase I clinical safety study. Specific Aim #1 proposes to evaluate AdFGF2 in a collagen-gelatin matrix for its ability to improve myocardial contractility in a dose-escalating efficacy study. Specific Aim #2 describes the development, scale-up and cGMP manufacture of bulk AdFGF2 to be utilized in pre-clinical and clinical studies. Specific Aim #3 describes evaluating acute toxicology and biodistribution in response to AdFGF2 in collagen-gelatin. Data generated will establish comprehensive efficacy and safety data in animals.