Graziewicz Maria A, Tarrant Teresa K, Buckley Brian, Roberts Jennifer, Fulton LeShara, Hansen Henrik, Ørum Henrik, Kole Ryszard, Sazani Peter
Ercole Biotech, Inc., Research Triangle Park, North Carolina, USA.
Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Mol Ther. 2008 Jul;16(7):1316-1322. doi: 10.1038/mt.2008.85. Epub 2016 Dec 8.
Tumor necrosis factor-α (TNF-α) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti-TNF-α drugs such as etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are a new class of drugs designed to induce therapeutically favorable splice variants of targeted genes. In this work, we used locked nucleic acid (LNA)-based SSOs to modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous expression from the membrane-bound, functional form to a soluble, secreted form (Δ7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-α, and altered disease in two mouse models: TNF-α-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-α antagonist by oligonucleotide-induced splicing modulation.
肿瘤坏死因子-α（TNF-α）是包括类风湿性关节炎（RA）在内的炎症性疾病的关键介质，而诸如依那西普等抗TNF-α药物是有效的治疗方法。剪接转换寡核苷酸（SSO）是一类新型药物，旨在诱导靶向基因产生治疗上有利的剪接变体。在这项研究中，我们使用基于锁核酸（LNA）的SSO来调节肿瘤坏死因子受体2（TNFR2）前体mRNA的剪接。该SSO诱导TNFR2第7外显子跳跃，该外显子编码跨膜结构域（TM），将内源性表达从膜结合的功能形式转变为可溶性分泌形式（Δ7TNFR2）。这种诱饵受体蛋白在经治疗小鼠的循环中积累，拮抗TNF-α，并在两种小鼠模型中改变疾病状况：TNF-α诱导的肝炎和胶原诱导的关节炎（CIA）。这是关于通过寡核苷酸诱导的剪接调节上调内源性循环TNF-α拮抗剂的首次报道。
