A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds
A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds
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DOI：
10.1111/wrr.12660
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发表时间：
2018-07-01
影响因子：
2.9
通讯作者：
Jackson, Aimee L.
中科院分区：
文献类型：
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作者：
Gallant-Behm, Corrie L.;Piper, Joseph;Jackson, Aimee L.
对于加速慢性和急性适应症伤口愈合的新疗法的强烈需求尚未得到满足。众所周知，局部组织缺氧、血管功能不全和/或血管生成不足会导致糖尿病足溃疡以及其他慢性伤口（例如静脉瘀血和压疮）的伤口修复不充分。 microRNA-92a-3p (miR-92a) 是一种有效的抗血管生成 miRNA，其抑制作用可导致多个器官系统的血管生成增加，从而改善心肌梗塞、肢体缺血、血管损伤和骨折后的功能。由于其促血管生成作用，miR-92a 抑制剂也提供了加速皮肤伤口愈合过程的潜在治疗方法。本研究调查了发育阶段锁定核酸修饰的 miR-92a 抑制剂 MRG-110 对 db/db 小鼠和正常猪切除伤口的影响。在急性和慢性伤口中，MRG-110 增加了通过组织学评估的肉芽组织形成、通过免疫组织化学和组织灌注评估的血管生成以及通过闭合时间和随时间推移的闭合百分比测量的伤口愈合。 MRG-110 的效果大于用阳性对照 rhVEGF-165 和 rhPDGF-BB 观察到的效果，并且当在 db/db 小鼠伤口中共同施用时，MRG-110 至少与 rhPDGF-BB 相加。研究发现，MRG-110 在体外人血管内皮细胞和原代人皮肤成纤维细胞中以及在体内小鼠皮肤中上调促血管生成 miR-92a 靶基因整合素 α 5 的表达，证明了其体外和体内的靶向作用。在小鼠和猪研究中评估了其他安全终点，没有注意到安全问题。这些研究表明MRG-110具有加速慢性和急性伤口愈合的潜力，这些数据为MRG-110未来的临床试验提供了支持。
There is a strong unmet need for new therapeutics to accelerate wound healing across both chronic and acute indications. It is well established that local tissue hypoxia, vascular insufficiency, and/or insufficient angiogenesis contribute to inadequate wound repair in the context of diabetic foot ulcers as well as to other chronic wounds such as venous stasis and pressure ulcers. microRNA-92a-3p (miR-92a) is a potent antiangiogenic miRNA whose inhibition has led to increases in angiogenesis in multiple organ systems, resulting in an improvement in function following myocardial infarction, limb ischemia, vascular injury, and bone fracture. Due to their pro-angiogenic effects, miR-92a inhibitors offer potential therapeutics to accelerate the healing process in cutaneous wounds as well. This study investigated the effect of a development stage locked nucleic acid-modified miR-92a inhibitor, MRG-110, in excisional wounds in db/db mice and in normal pigs. In both acute and chronic wounds, MRG-110 increased granulation tissue formation as assessed by histology, angiogenesis as assessed by immunohistochemistry and tissue perfusion, and wound healing as measured by time to closure and percent closure over time. The effects of MRG-110 were greater than those that were observed with the positive controls rhVEGF-165 and rhPDGF-BB, and MRG-110 was at least additive with rhPDGF-BB when co-administered in db/db mouse wounds. MRG-110 was found to up-regulate expression of the pro-angiogenic miR-92a target gene integrin alpha 5 in vitro in both human vascular endothelial cells and primary human skin fibroblasts and in vivo in mouse skin, demonstrating its on-target effects in vitro and in vivo. Additional safety endpoints were assessed in both the mouse and pig studies with no safety concerns noted. These studies suggest that MRG-110 has the potential to accelerate both chronic and acute wound healing and these data provide support for future clinical trials of MRG-110.