Yadav Sanjeev Kumar, Dhuri Karishma, Gamiotea-Turro Daylin, Cormier Mary-Katherine, Patel Vraj, Yadawa Arun Kumar, Pathuri Mounika, Bahal Raman, Verma Rajkumar
Department of Neuroscience, UConn Health, Farmington, CT 06032, USA.
School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Mol Ther Nucleic Acids. 2024 Oct 9;35(4):102355. doi: 10.1016/j.omtn.2024.102355. eCollection 2024 Dec 10.
MicroRNA-141-3p plays a detrimental role in the pathology of ischemic stroke, presenting a new target for stroke treatment. This study introduces and validates a novel class of peptide nucleic acid (PNA)-based miR-141-3p inhibitors known as serine gamma PNA-141 (sγPNA-141) for ischemic stroke treatment. After synthesis, physicochemical characterization, and nanoparticle encapsulation of sγPNA-141, we compared its safety and efficacy with traditional phosphorothioate- and regular PNA-based anti-miR-141-3p (PNA-141) , followed by detailed and efficacy testing of sγPNA-141 for treating ischemic stroke using a mouse model. sγPNA-141 demonstrated higher affinity and specificity toward miR-141-3p, and when applied post-stroke, demonstrated decreased brain damage, enhanced neuroprotective proteins, reduced tissue atrophy, swift improvement in functional deficits, and improvement in learning and memory during long-term recovery. Overall, our data show sγPNA-141 has neuroprotective and neuro-rehabilitative effects during stroke recovery. Furthermore, we demonstrated sγPNA-141's effects are mediated by the TGF-β-SMAD2/3 pathway. In summary, the present findings suggest that sγPNA-141 could be a potentially novel and effective therapeutic modality for the treatment of ischemic stroke.
微小RNA-141-3p在缺血性中风的病理过程中起有害作用，这为中风治疗提供了一个新靶点。本研究引入并验证了一类新型的基于肽核酸（PNA）的miR-141-3p抑制剂，即丝氨酸γ肽核酸-141（sγPNA-141），用于缺血性中风的治疗。在对sγPNA-141进行合成、理化特性表征及纳米颗粒包封后，我们将其安全性和有效性与传统的硫代磷酸酯类和常规PNA类抗miR-141-3p（PNA-141）进行了比较，随后使用小鼠模型对sγPNA-141治疗缺血性中风进行了详细的安全性和有效性测试。sγPNA-141对miR-141-3p表现出更高的亲和力和特异性，在中风后应用时，可减少脑损伤、增强神经保护蛋白、减轻组织萎缩、迅速改善功能缺陷，并在长期恢复过程中改善学习和记忆。总体而言，我们的数据表明sγPNA-141在中风恢复过程中具有神经保护和神经修复作用。此外，我们证明了sγPNA-141的作用是由TGF-β-SMAD2/3信号通路介导的。综上所述，本研究结果表明sγPNA-141可能是一种潜在的新型有效治疗缺血性中风的方法。
