Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists

描述(申请人提供)：尽管Folkman最初提出的抗血管生成将是癌症化疗的有效方法的想法受到了几乎所有人的怀疑，但这一概念现在已被广泛接受，不仅构成了癌症治疗的基础，而且还构成了Folkman总结的一系列非肿瘤性疾病的治疗基础，Folkman将其概括为“血管生成依赖型疾病”。目前批准的针对参与血管生成的中枢身体化学物质血管内皮生长因子的疗法是有用的，但并不完全安全或有效。我们建议通过发现有效的噬菌体展示方法来开发新的抗血管内皮生长因子药物，并将这些新药物应用于下一代安全有效的血管生成抑制剂。我们的具体目标是：(I)发现和开发新的以血管内皮生长因子受体家族为靶点的抗血管生成多肽化合物，以及(Ii)设计和测试用于视网膜血管生成治疗控制的新药物。这些药物都会选择性地与病理性的新血管结合，并阻断或摧毁它们，而不会影响正常的血管。我们的目标是了解和抑制人类致盲疾病的实验性小鼠模型神经视网膜中的病理性血管生成。

DESCRIPTION (provided by applicant): Despite the near-universal skepticism that initially greeted Folkman's presentation of his idea that anti-angiogenesis would be an effective approach to cancer chemotherapy, this concept has now become widely accepted and forms a basis not only for cancer therapy, but also for therapy of a broad range of non-neoplastic disorders that Folkman summarizes under the term 'angiogenesis-dependent diseases'. Currently approved therapies, directed against the central bodily chemical involved in angiogenesis, VEGF, are useful, but not entirely safe or effective. We propose to develop new anti-VEGF agents through discovery by powerful phage display methods, and to apply these new agents as a forthcoming generation of safe and effective angiogenesis inhibitors. Our specific aims are: (i) to discover and develop new anti-angiogenic peptidomimetic compounds targeting the VEGF receptor family, and (ii) to design and test new agents for therapeutic control of retinal angiogenesis. These agents would both bind selectively to pathological new blood vessels and block or destroy them, without affecting normal blood vessels. Our goal is to understand and inhibit pathological angiogenesis in the neural retina of experimental mouse models of human blindness-causing diseases.