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，但许多患者不适合这些手术。新的治疗方法，如“治疗性血管生成”，其中生长因子蛋白质或基因用于诱导缺血心肌的血管重建，可能提供所需的替代方案。在I期研究中，我们启动了血运重建基因治疗的开发。载体编码血管生成基因碱性成纤维细胞生长因子（FGF 2）的胶原基基质中配制，并在交付缺血心肌诱导新血管形成和心肌收缩力的恢复。我们现在建议通过高级临床前研究继续这项工作，旨在实现IND提交和启动I期临床安全性研究。具体目标#1提出在剂量递增功效研究中评价胶原-明胶基质中的AdFGF 2改善心肌收缩性的能力。具体目标#2描述了用于临床前和临床研究的散装AdFGF 2的开发、规模扩大和cGMP生产。具体目标#3描述了评价胶原-明胶中响应于AdFGF 2的急性毒理学和生物分布。生成的数据将建立动物中的全面有效性和安全性数据。

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.