MARVEL试验:一项口服MitoQ治疗中度溃疡性结肠炎的2b期随机安慰剂对照试验

IF 4.1 Q2 IMMUNOLOGY Immunotherapy advances Pub Date : 2020-11-12 DOI:10.1093/immadv/ltaa002
Emily Gwyer Findlay, G. Sutton, G. Ho
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引用次数: 8

摘要

溃疡性结肠炎(UC)是一种大肠炎症性疾病,其特征是免疫失调和肠道上皮细胞死亡,导致炎症延长。这最终可能导致手术切除大肠,如果炎症持续存在,就有患癌症的风险。目前的治疗方法——针对传入的免疫细胞或它们产生的细胞因子——正在显著改善,但它们价格昂贵且具有免疫抑制性,导致感染风险。在这里,我们讨论了一项新的试验,该试验针对炎症的早期诱导物——线粒体产生活性氧(ROS)。先前的研究表明,过量的线粒体ROS通过cGAS-STING途径诱导炎症信号传导,导致免疫失调和上皮细胞死亡。在这项MARVEL试验(线粒体抗氧化疗法解决溃疡性结肠炎炎症)中,除了标准药物治疗外,患有活动性UC发作的患者还将服用线粒体抗氧化(MitoQ)或安慰剂,以抑制炎症的发展。这项2b期试验将重新利用MitoQ,MitoQ之前曾在不同疾病环境中的其他大型试验中进行过测试,并将在24周内测量临床反应和炎症标志物。希望这项试验将通过重新利用一种相对便宜、无毒且特性良好的药物,为UC开发一个新的靶点。
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The MARVEL trial: a phase 2b randomised placebo-controlled trial of oral MitoQ in moderate ulcerative colitis
Summary Ulcerative colitis (UC) is an inflammatory disease of the large bowel which is characterised by dysregulated immunity and death to epithelial cells in the bowel, leading to prolonged inflammation. This can ultimately lead to surgery to remove the large bowel, with a risk of cancer developing if inflammation persists. Current therapies – which target the incoming immune cells or the cytokines they produce – are improving significantly but they are expensive and are immunosuppressive, leading to risk of infection. Here, we discuss a new trial which targets an early inducer of inflammation – the production of reactive oxygen species (ROS) by mitochondria. Previous work has shown that excessive mitochondrial ROS induces inflammatory signalling through the cGAS-STING pathway, leading to dysregulated immunity and death of epithelial cells. In this MARVEL trial (Mitochondrial Anti-oxidant therapy to Resolve Inflammation in Ulcerative Colitis) individuals with an active UC flare-up will be given a mitochondrial anti-oxidant (MitoQ) or placebo tablet in addition to standard medical treatment, in order to suppress inflammation as it develops. This phase 2b trial will repurpose MitoQ, which has been previously tested in other large trials in different disease settings, and will measure clinical response and markers of inflammation over 24 weeks. It is hoped that this trial will develop a new target for UC through re-purposing a relatively cheap, non-toxic and well-characterised drug.
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