Ichor Life Sciences Inc, Lafayette, USA.
Clarkson University, Potsdam, USA.
Sci Rep. 2023 Jun 19;13(1):9923. doi: 10.1038/s41598-023-36933-4.
Chronic wounds are characterized by a persistent, hyper-inflammatory environment that prevents progression to regenerative wound closure. Such chronic wounds are especially common in diabetic patients, often requiring distal limb amputation, but occur in non-diabetic, elderly patients as well. Induced expression of HoxA3, a member of the Homeobox family of body patterning and master regulatory transcription factors, has been shown to accelerate wound closure in diabetic mice when applied topically as a plasmid encased in a hydrogel. We now provide independent replication of those foundational in vivo diabetic wound closure studies, observing 16% faster healing (3.3 mm wounds vs 3.9 mm wounds at Day 9 post original injury of 6 mm diameter) under treatment with observable microscopic benefits. We then expand upon these findings with minimal dose threshold estimation of 1 μg HoxA3 plasmid delivered topically at a weekly interval. Furthermore, we observed similarities in natural wound healing rates between aged non-diabetic mice and young diabetic mice, which provided motivation to test topical HoxA3 plasmid in aged non-diabetic mice. We observed that HoxA3 treatment achieved complete wound closure (0 mm diameter) at 2 weeks whereas untreated wounds were only 50% closed (3 mm wound diameter). We did not observe any gross adverse effects macroscopically or via histology in these short studies. Whether as a plasmid or future alternative modality, topical HoxA3 is an attractive translational candidate for chronic wounds.
慢性伤口的特征是持续存在的、过度炎症的环境，这会阻止伤口向再生性愈合的方向发展。这种慢性伤口在糖尿病患者中尤为常见，往往需要进行远端肢体截肢，但也会在非糖尿病的老年患者中发生。研究表明，在糖尿病小鼠中，局部应用包裹在水凝胶中的质粒来诱导同源盒 A3（HOXA3）的表达，可加速伤口闭合，HOXA3 是同源盒家族中身体模式和主要调控转录因子的成员。我们现在提供了这些基础的体内糖尿病伤口闭合研究的独立复制，观察到在治疗下，伤口愈合速度加快了 16%（直径为 6mm 的原始损伤后第 9 天，3.3mm 伤口 vs. 3.9mm 伤口），并观察到明显的微观益处。然后，我们在每周间隔局部给予 1μg HOXA3 质粒的最小剂量阈值估计的基础上，对这些发现进行了扩展。此外，我们观察到年龄非糖尿病小鼠和年轻糖尿病小鼠的自然伤口愈合率相似，这促使我们在年龄非糖尿病小鼠中测试局部 HOXA3 质粒。我们观察到，HOXA3 治疗在 2 周时达到完全伤口闭合（0mm 直径），而未治疗的伤口仅闭合 50%（3mm 伤口直径）。在这些短期研究中，我们没有观察到宏观或组织学上的任何明显不良反应。无论是作为质粒还是未来的替代方式，局部应用 HOXA3 是治疗慢性伤口的一种有吸引力的转化候选物。
