TREATMENT OF PERIPHERAL ARTERIAL DISEASE WITH VEGF 121

描述：血管内皮生长因子(VEGF)是一种高度内皮细胞特异性的有丝分裂原，能够刺激体内新血管的生长(血管生成)和侧支依赖的血流。由于这些特性，血管内皮生长因子已被认为是一种治疗外周动脉疾病的潜在药物疗法。在五种不同剪接变异的血管内皮生长因子亚型中，只有最短的(VEGF121)缺乏结合肝素样分子的能力。该项目第一阶段的实验证实，VEGF121和其他血管内皮生长因子亚型一样，在体内活跃于促进侧支循环的血流。此外，与其缺乏肝素结合一致，VEGF121被发现显示出药代动力学和清除特性，这可能为使用这种异构体赋予特殊的治疗优势。在该项目的第二阶段，VEGF121将推进最终的临床疗效测试和对这些潜在优势的验证。特别是，将为该药物开发一种制造工艺。还将进行进一步的实验，以更好地确定VEGF121在外周动脉供血不足动物模型中的作用。拟议的商业应用：这项研究的最终目标是开发一种治疗外周动脉疾病的治疗剂。

DESCRIPTION (Verbatim from the applicant's abstract): Vascular endothelial growth factor (VEGF) is a highly endothelial cell-specific mitogen capable of stimulating new blood vessel growth (angiogenesis) and collateral- dependent blood flow in vivo. Because of these properties, VEGF has been proposed as a potential pharmacological therapy for the treatment of peripheral arterial disease. Among the five different splice variant isoforms of VEGF, only the shortest (VEGF121) lacks the ability to bind heparin-like molecules. Experiments during Phase I of the project established that VEGF121, like other VEGF isoforms, is active in vivo for the promotion of collateral-dependent blood flow. In addition, consistent with its lack of heparin binding, VEGF121 was found to display pharmacokinetic and clearance characteristics that may confer particular therapeutic advantages to the use of this isoform. During Phase II of the project, VEGF121 will be advanced toward eventual clinical testing of efficacy and of validation for these potential advantages. In particular, a manufacturing process will be developed for the drug. Further experiments will also be undertaken to better define the effects of VEGF121 in an animal model of peripheral arterial insufficiency. PROPOSED COMMERCIAL APPLICATION: The research is ultimately aimed at developing a therapeutic agent for the treatment of peripheral arterial disease.