Targeted nanoparticle delivery of PNA anti-miRs to quiesce inflamed endothelium

 描述（由申请人提供）：内皮炎症现在被认为是许多形式的心血管疾病的重要影响因素，并且已成为许多正在开发的疗法的焦点。几种 microRNA (miRNA) 已被确定在人内皮细胞对促炎信号的反应中发挥关键调节作用，这表明旨在抑制这些 miRNA 活性的反义疗法可能是一种可行的治疗方法。事实上，最近的动物模型研究已经证明原理证明，抑制促炎 miRNA（例如 miR-92a）可以成为解决内皮炎症的有效策略。尽管这些研究带来了希望，但将抗 miRNA 药物从动物模型转化为能够逆转人类心血管疾病慢性炎症的疗法仍存在重大障碍。最值得注意的是，全身施用的抗 miRNA 药物的药代动力学特性和生物分布相当差。这些问题的一种解决方案是将抗 miRNA 分子包装在纳米级递送载体中，该载体能够确保药物被输送到发炎的脉管系统并维持在发炎的脉管系统内。在本提案中，我们的目标是开发一种聚合物纳米颗粒递送平台，能够递送持续水平的基于肽核酸的抗 miR-92a 药物。纳米粒子将通过与E-选择素（一种在某些发炎内皮上上调的粘附分子）抗体结合而在分子上靶向炎症部位。为了帮助弥合动物模型与实现的人类治疗之间的差距，我们将采用人源化小鼠模型，使我们能够在体内环境中瞄准和治疗发炎的人类脉管系统。如果成功，这些实验将加速安全有效的抗 miRNA 疗法的开发，以解决许多心血管疾病潜在的炎症。

 DESCRIPTION (provided by applicant): Endothelial inflammation is now appreciated to be a significant contributing factor in many forms of cardiovascular disease and has become the focal point of many developing therapies. Several microRNAs (miRNAs) have been identified as playing key regulatory roles in the response of human endothelium to pro- inflammatory cues, suggesting that anti-sense therapies designed to inhibit the activity of these miRNAs may be a viable therapeutic approach. Indeed, recent studies in animal models have demonstrated proof of principle that inhibition of pro-inflammatory miRNAs, such as miR-92a, can be an effective strategy for resolving endothelial inflammation. In spite of the promise these studies provide, there exist major impediments to the translation of anti-miRNA agents from animal models to therapies capable of reversing chronic inflammation in human cardiovascular disease. Most notably, the pharmacokinetic properties and biodistribution of systemically administered anti-miRNA agents are quite poor. One solution to these issues is packaging the anti- miRNA molecules within nanoscale delivery vehicles that are capable of ensuring that the drugs are routed to and maintained within the inflamed vasculature. In this proposal we aim to develop a polymeric nanoparticle delivery platform capable of delivering sustained levels of a peptide-nucleic-acid based anti-miR-92a agent. The nanoparticles will be molecularly targeted to sites of inflammation via conjugation of antibodies to E- selectin, an adhesion molecule upregulated on certain inflamed endothelium. In order to help bridge the gap from animal models to a realized human therapy, we will employ humanized mice models allowing us to target and treat inflamed human vasculature within an in vivo setting. If successful, these experiments will hasten the development of safe and effective anti-miRNA therapies for resolving the inflammation underlying many cardiovascular diseases.