Wang Zhuo, Sriram Sriniwas, Ugwoke Cynthia, Gale Zoe, Tabrizi Maral, Griffin Martin
School of Biosciences, College of Health and Life Sciences, Aston Triangle, Aston University, Birmingham B4 7ET, UK.
Isterian Biotech, Inc., 228 Park Ave S, #66643, New York, NY 10003, USA.
Cells. 2025 Mar 26;14(7):497. doi: 10.3390/cells14070497.
This paper investigates the ability of our selective small molecule TG2 inhibitor 1-155 in reducing fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. Formulated as a fine stable suspension, 1-155 was delivered intranasally (IN) at 3 mg/kg via IN delivery once daily. It significantly inhibited collagen deposition in the lungs in the bleomycin-challenged mice. Compared to its vehicle control treatment, a significant reduction in a key myofibroblast marker α smooth muscle actin and TG2 was also detected in the 1-155-treated animals. Most importantly, 1-155 treatment significantly improved several key lung function parameters, such as cord compliance, vital capacity, and dynamic compliance, which are comparable to that found for the positive control nintedanib at a much higher dosage of 60 mg/kg twice daily via oral delivery. The 1-155-treated mice showed a trend in improvement of average body weight. For the first time, our study demonstrates the effectiveness of a selective small molecule TG2 inhibitor in reducing pulmonary fibrosis in a pre-clinical model. Importantly, we were able to correlate this effect of 1-155 with the improvement of animal lung function showing the potential of the use of TG2 inhibitors as a therapeutic treatment for fibrotic lung conditions like IPF.
本文研究了我们的选择性小分子TG2抑制剂1-155在博来霉素诱导的肺纤维化小鼠模型中减轻纤维化的能力。1-155被配制成精细稳定的悬浮液，通过鼻内给药（IN）以3 mg/kg的剂量每日给药一次。它显著抑制了博来霉素攻击的小鼠肺部的胶原蛋白沉积。与载体对照治疗相比，在接受1-155治疗的动物中还检测到关键的肌成纤维细胞标志物α平滑肌肌动蛋白和TG2显著减少。最重要的是，1-155治疗显著改善了几个关键的肺功能参数，如肺顺应性、肺活量和动态顺应性，这与通过口服给药以每天两次、剂量高达60 mg/kg的阳性对照尼达尼布所发现的情况相当。接受1-155治疗的小鼠平均体重有改善的趋势。我们的研究首次证明了选择性小分子TG2抑制剂在临床前模型中减轻肺纤维化的有效性。重要的是，我们能够将1-155的这种作用与动物肺功能的改善联系起来，表明TG2抑制剂作为治疗如特发性肺纤维化等纤维化肺部疾病的治疗方法的潜力。
