Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy.
Curr Drug Targets. 2013 Nov;14(12):1400-4. doi: 10.2174/13894501113149990157.
Crohn's disease (CD) and ulcerative colitis (UC), two chronic and relapsing inflammatory bowel diseases (IBD), are supposed to develop in genetically-predisposed individuals as a result of an excessive immune mucosal response directed against normal components of the gut microbiota. There is also evidence that defects in counter-regulatory mechanisms play a major role in the pathogenesis of IBD. One such a defect involves TGF-β1, a cytokine produced by multiple cells types and able to inhibit pathogenic responses in the gut. In both CD and UC, TGF-β1 is highly produced but unable to signal through the TGF-β receptor-associated Smad pathway and suppress production of inflammatory molecules. Abrogation of TGF-β1 activity has been related to Smad7, an intracellular protein that binds to TGF-β receptor and inhibits TGF-β1-driven Smad-dependent signalling. Indeed, silencing of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad signalling, thereby down-regulating inflammatory cytokine production and ameliorating experimental colitis in mice. Altogether these observations led to the development of an oral pharmaceutical compound containing the specific Smad7 antisense oligonucleotide (herein termed GED0301), which seems to be safe and well tolerated in CD patients. In this article we summarize the data supporting the pathogenic role of Smad7 in IBD and discuss the recent results of the use of GED0301 in CD.
克罗恩病（CD）和溃疡性结肠炎（UC）是两种慢性复发性炎症性肠病（IBD），被认为是由于针对肠道微生物群正常成分的过度免疫黏膜反应，在遗传易感性个体中发展起来的。也有证据表明，代偿性机制缺陷在 IBD 的发病机制中起主要作用。这样的缺陷之一涉及 TGF-β1，这是一种由多种细胞类型产生的细胞因子，能够抑制肠道中的致病反应。在 CD 和 UC 中，TGF-β1 大量产生，但无法通过 TGF-β 受体相关的 Smad 途径发出信号，并抑制炎症分子的产生。TGF-β1 活性的缺失与 Smad7 有关，Smad7 是一种细胞内蛋白，可与 TGF-β 受体结合并抑制 TGF-β1 驱动的 Smad 依赖性信号转导。事实上，用特异性反义寡核苷酸沉默 Smad7 可恢复 TGF-β1/Smad 信号转导，从而下调炎症细胞因子的产生并改善小鼠实验性结肠炎。总之，这些观察结果导致了一种含有特异性 Smad7 反义寡核苷酸的口服药物的开发（在此称为 GED0301），它在 CD 患者中似乎是安全且耐受良好的。在本文中，我们总结了支持 Smad7 在 IBD 中致病作用的研究数据，并讨论了 GED0301 在 CD 中的最新应用结果。
