DNA methylation markers to predict treatment success of biologicals in Crohn’s disease

DNA 甲基化标记可预测克罗恩病生物制剂的治疗成功率

• 批准号: 10065237
• 金额: $ 41.9万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10065237
• 关键词: DNA; methylation; markers; predict; treatment

Monoclonal antibodies have become a mainstay of therapy in common immune-mediated diseases (IMID) including Crohn’s disease (CD), rheumatoid arthritis (RA), and psoriasis (PsO). Current therapeutics include antibodies (“biologicals”) targeting inflammatory proteins such as Tumor Necrosis Factor (adalimumab), leukocyte trafficking (vedolizumab), or IL-12/IL-23 (ustekinumab). At present however, it cannot be predicted which biological will be effective in an individual patient, with only <40% of patients showing primary response to any given therapeutic. Treatment failure is associated with disease complications, and increased health care costs.. Hence the overwhelming need for predictive biomarkers to guide personalised medicine in IMID is evident. No biomarker to target therapy is validated in clinical practice. In METHYLOMIC, we build on multiple previous cohort studies in which we confirmed epigenetic biomarkers (specifically DNA methylation) as the most stringent predictor of response to biological therapy, zooming in on CD. Specifically, we discovered and validated differential DNA methylation profiles in peripheral blood as biomarkers of response/deep remission for 3 approved biologicals in CD. Through the use of machine learning algorithms, treatment response could be predicted with up to 93% accuracy for each biological for CD, and RA. METHYLOMICS is committed to bringing personalised treatment-selection in CD and other IMID to clinical practice. We have teamed up clinical, epigenetic, and DNA diagnostics experts, patient organisations, and companies across Europe, for further validation studies, develop a marketable rapid targeted methylation assay that we than validate in a unique prospective randomised clinical trial for CD. Efficiency and cost-effectiveness is assessed in great detail and regulatory approval is guided by experts to assure delivery of the first epigenetic kit personalised treatment of CD

单克隆抗体已成为常见免疫介导疾病（IMID）（包括克罗恩病（CD）、类风湿性关节炎（RA）和银屑病（PsO））的主要治疗手段。目前的治疗剂包括靶向炎性蛋白的抗体（“生物制剂”），如肿瘤坏死因子（阿达木单抗）、白细胞运输（维多珠单抗）或IL-12/IL-23（优特克单抗）。然而，目前无法预测哪种生物制剂对个体患者有效，只有<40%的患者对任何给定的治疗剂显示出主要反应。治疗失败与疾病并发症有关，并增加了医疗保健费用。因此，对预测性生物标志物的压倒性需求，以指导IMID的个性化药物是显而易见的。在临床实践中没有对靶向治疗的生物标志物进行验证。在METHYLOMIC中，我们建立在多个先前的队列研究基础上，在这些研究中，我们证实了表观遗传生物标志物（特别是DNA甲基化）是对生物治疗反应的最严格预测因子，放大了CD。具体而言，我们发现并验证了外周血中的差异DNA甲基化谱作为3种获批生物制剂治疗CD的缓解/深度缓解的生物标志物。通过使用机器学习算法，可以预测CD和RA每种生物学的治疗反应，准确率高达93%。METHYLOMICS致力于将CD和其他IMID的个性化治疗选择带入临床实践。我们已经与欧洲各地的临床、表观遗传学和DNA诊断专家、患者组织和公司合作，进行进一步的验证研究，开发出一种可销售的快速靶向甲基化检测方法，并在一项独特的CD前瞻性随机临床试验中进行验证。效率和成本效益进行了非常详细的评估，并由专家指导监管批准，以确保提供第一个CD的表观遗传试剂盒个性化治疗