Exploring the therapeutic potential of sγPNA-141: Pharmacodynamics and mechanistic insights during ischemic stroke recovery

• Published in: Molecular therapy. Nucleic acids Vol. 35; no. 4; p. 102355
• Main Authors: Yadav, Sanjeev Kumar, Dhuri, Karishma, Gamiotea-Turro, Daylin, Cormier, Mary-Katherine, Patel, Vraj, Yadawa, Arun Kumar, Pathuri, Mounika, Bahal, Raman, Verma, Rajkumar
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10-12-2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: anti-miR-141-3p; ischemic stroke; Middle cerebral artery occlusion; MiRNA; MT: Non-coding RNAs; nanoparticles; neuroprotection: Neuroinflammation; Original; serine gamma peptide nucleic acid; TFGβ/SMAD signaling; anti-miR-141-3p; nanoparticles; neuroprotection: Neuroinflammation; TFGβ/SMAD signaling; Middle cerebral artery occlusion; MiRNA; serine gamma peptide nucleic acid; MT: Non-coding RNAs; ischemic stroke
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2024.102355

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) in vitro, followed by detailed in vivo and ex vivo 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.
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Verma and colleagues present sγPNA-141, a novel peptide nucleic acid based miR-141-3p, as an effective treatment for ischemic stroke. It outperformed traditional inhibitors both in vitro and in vivo, reducing brain damage and enhancing recovery through the TGF-β-SMAD2/3 pathway.