Cardium Therapeutics, Inc., San Diego, California 92130, USA.
Mol Ther. 2013 Apr;21(4):725-38. doi: 10.1038/mt.2013.13. Epub 2013 Feb 12.
Stimulation of collateral vessel development in the heart by angiogenic growth factor therapy has been tested in animals and humans for almost two decades. Discordance between the outcome of preclinical studies and clinical trials pointed to the difficulties of translation from animal models to patients. Lessons learned in this process identified specific mechanistic, technical, and clinical hurdles, which need to be overcome. This review summarizes current understanding of the mechanisms leading to the establishment of a functional coronary collateral network and the biological processes growth factor therapies should stimulate even under conditions of impaired natural adaptive vascular response. Vector delivery methods are recommended to maximize angiogenic gene therapy efficiency and reduce side effects. Optimization of clinical trial design should include the choice of clinical end points which provide mechanistic proof-of-concept and also reflect clinical benefits (e.g., surrogates to assess increased collateral flow reserve, such as myocardial perfusion imaging). Guidelines are proposed to select patients who may respond to the therapy with high(er) probability. Both short and longer term strategies are outlined which may help to make therapeutic angiogenesis (TA) work in the future.
近二十年来，人们一直在动物和人体中测试血管生成生长因子疗法对心脏侧支血管发育的刺激作用。临床前研究和临床试验结果之间的差异表明，从动物模型向患者的转化存在困难。在这一过程中吸取的经验教训确定了需要克服的特定机制、技术和临床障碍。这篇综述总结了目前对导致功能性冠状动脉侧支网络建立的机制的理解，以及在自然适应性血管反应受损的情况下，生长因子疗法应该刺激的生物学过程。建议使用载体传递方法来最大限度地提高血管生成基因治疗的效率并减少副作用。临床试验设计的优化应包括选择提供机制概念验证并反映临床益处的临床终点（例如，评估侧支血流储备增加的替代指标，如心肌灌注成像）。提出了选择可能对治疗有较高反应概率的患者的指南。概述了短期和长期策略，这些策略可能有助于未来使治疗性血管生成（TA）发挥作用。
