Pradeep Sai Pallavi, Kumar Vikas, Malik Shipra, Slack Frank J, Gupta Anisha, Bahal Raman
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Department of Pathology, HMS Initiative for RNA Medicine, BIDMC Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep Phys Sci. 2024 Aug 21;5(8). doi: 10.1016/j.xcrp.2024.102120. Epub 2024 Jul 29.
We explore the potential of clamp-G nucleobase-modified peptide nucleic acids (cGPNAs) as microRNA and messenger RNA inhibitors. For proof of concept, we target miR-155, which is upregulated in diffuse large B cell lymphoma. cGPNA shows significant downregulation of miR-155 and the upregulation of its downstream targets in multiple lymphoma cell lines. Also, cGPNA treatment reduced tumor growth and improved survival in the U2932 cell-derived xenograft mouse model. To assess the broad application of cGPNA as an antisense modality, we also target transthyretin () mRNA. We establish a dose-dependent effect of antisense cGPNA on mRNA levels. For studies, we conjugated cGPNA-based TTR antisense with lactobionic acid-based targeting ligand for liver delivery. We establish that cGPNA exhibits significant TTR protein knockdown compared to unmodified peptide nucleic acid (PNA) . Overall, we confirm that clamp-G-modified PNA analogs are a robust antisense therapy platform.
我们探索了钳夹-G核碱基修饰的肽核酸（cGPNAs）作为微小RNA和信使RNA抑制剂的潜力。为了验证概念，我们以弥漫性大B细胞淋巴瘤中上调的miR-155为靶点。cGPNA在多种淋巴瘤细胞系中显示出miR-155的显著下调及其下游靶点的上调。此外，在U2932细胞衍生的异种移植小鼠模型中，cGPNA治疗减少了肿瘤生长并提高了生存率。为了评估cGPNA作为反义方式的广泛应用，我们还以转甲状腺素蛋白（TTR）mRNA为靶点。我们建立了反义cGPNA对TTR mRNA水平的剂量依赖性效应。对于体内研究，我们将基于cGPNA的TTR反义与基于乳糖醛酸的靶向配体偶联用于肝脏递送。我们证实，与未修饰的肽核酸（PNA）相比，cGPNA表现出显著的TTR蛋白敲低。总体而言，我们证实钳夹-G修饰的PNA类似物是一个强大的反义治疗平台。
