Phase I Clinical Trial of Smad7 Knockdown Using Antisense Oligonucleotide in Patients With Active Crohn's Disease
Phase I Clinical Trial of Smad7 Knockdown Using Antisense Oligonucleotide in Patients With Active Crohn's Disease
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DOI：
10.1038/mt.2011.290
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发表时间：
2012-04-01
影响因子：
12.4
通讯作者：
Pallone, Francesco
中科院分区：
文献类型：
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作者：
Monteleone, Giovanni;Fantini, Massimo C.;Pallone, Francesco
在克罗恩病（CD）患者的肠道中，高水平的Smad7阻断了转化生长因子(TGF)- β 1的免疫抑制活性，从而有助于放大炎症信号。在小鼠体内，用Smad7反义寡核苷酸（GED0301）敲除Smad7可减轻实验性结肠炎。在这里，我们提供了GED0301在活动性、类固醇依赖/耐药CD患者中的1期临床、开放标签、剂量递增研究的结果，旨在评估该药的安全性和耐受性。患者被分配到三个治疗组，每天一次口服GED0301，剂量为40,80或160mg，持续7天。共有15名患者入组。未发生严重不良事件。GED0301耐受性良好，在研究期间没有患者退出。在11例患者中记录了25个不良事件，其中大多数被判断为轻度强度，与治疗无关。GED0301治疗降低了血液中表达炎症细胞因子ccr9阳性T细胞的百分比。该研究首次表明GED0301在活动性CD患者中是安全且耐受性良好的。
In the gut of patients with Crohn's disease (CD), high Smad7 blocks the immune-suppressive activity of transforming growth factor (TGF)-beta 1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD.