Genetic predictors of calprotectin response with anti-TNF and anti-integrin therapy in inflammatory bowel diseases

炎症性肠病中抗 TNF 和抗整合素治疗钙卫蛋白反应的遗传预测因子

基本信息

批准号：
9291719
负责人：
Ashwin N Ananthakrishnan
金额：
$ 8.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9291719
关键词：
Accounting Achievement Adverse event Affect Age of Onset American Anti-Tumor Necrosis Factor Therapy Antibodies Behavior Biochemical Caring Categories Chronic Clinical Clinical Data Collaborations Collection Crohn&apos s disease Data Development Disease Disease Management Disease remission Ensure Feces Foundations Funding Future Genetic Genetic Markers Genetic Polymorphism Genetic Risk Genotype Goals Grant Health Care Costs Hospitalization Immune Immune Targeting Immune response Immunology Immunosuppression Impairment Individual Infection Inflammation Inflammatory Bowel Diseases Inflammatory disease of the intestine Integrins Interleukin-12 Intestines Janus kinase Leukocyte L1 Antigen Complex Leukocyte Trafficking Location Malignant Neoplasms Measures Mediating Metagenomics Modeling Monoclonal Antibodies Morbidity - disease rate Operative Surgical Procedures Outcome Pathway interactions Patients Performance Pharmacogenetics Phenotype Predictive Value Prospective cohort Quality of life Relapse Research Infrastructure Research Personnel Resistance Sampling Severities Smoking Societies Symbiosis Symptoms TNF gene Therapeutic Therapeutic immunosuppression Ulcerative Colitis United States Work adjudicate adjudication base cohort comparative effectiveness disability effective therapy factor A genetic predictors gut microbiome illness length immunoregulation improved individual patient inflammatory marker innovation insight microbial mucosal addressin cell adhesion molecule-1 novel personalized care predicting response predictive modeling predictive tools prospective response risk variant success therapy resistant tool treatment choice treatment response vascular addressins

项目摘要

Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediate diseases that affect an estimated 1.5 million Americans and account for 1.5 million in direct healthcare costs. Due to their young age of onset and protracted course characterized by relapses, hospitalizations, and surgery, they exert a considerable toll on patients and society. Therapeutic advances with the availability of monoclonal antibodies against tumor necrosis factor α (anti- TNF) and anti-integrin (vedolizumab) therapies have made achievement of durable clinical and endoscopic remission increasingly possible. However, one-fifth of patients fail to achieve even an initial response and a similar proportion response annually. At present, choice of therapy is largely non-selective with sequential trial of agents from different therapeutic classes without a priori prediction of likelihood of response. However, this results in protracted morbidity due to inadequate treatment of disease and increases likelihood of permanent bowel damage in addition to exposing patients to ineffective but potentially toxic agents. Thus, there is an important unmet need for tools to predict response to each individual therapeutic class. Clinical factors such as smoking, duration of disease, location and behavior of involvement, have proved inconsistent in predicting response to therapy. In our previous work, we developed a prediction tool using genetic risk alleles to identify primary and secondary non-responders to anti-TNF therapy. This tool demonstrated both the utility of genetics and superiority of it as a predictor compared to clinical data. However, limitations to that work include retrospective adjudication of treatment response categories and reliance on improvement of symptoms which correlate poorly with endoscopic severity of inflammation, arguably a more robust marker. In this proposal, we aim to validate our prediction tool in an independent prospective cohort of patients initiating anti-TNF therapy, and important to assess its utility in determining response based on change and normalization of fecal calprotectin, a sensitive objective marker of intestinal inflammation. In addition, with the goal of developing tools to aid in personalized precise therapy by identifying mechanisms of action most likely to be of benefit to each patient, we will examine the predictive value of our existing therapy response tool in a prospective cohort of patients on treatment with vedolizumab. If our existing model is unable to predict response to vedolizumab, we will develop a separate predictive model with distinct polymorphisms to predict response to this therapeutic class. Importantly, the insights from this proposal will serve as a foundation for development of a comprehensive predictive model that also incorporates composition and metagenomic function of the gut microbiome that will significantly further our aim of providing personalized, precise care to our patients and ensuring optimal outcomes. This grant will also provide important preliminary data in support of the applicants future independent R01 funding proposal, and is a critically important step in the long-term academic success of the applicant.

克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是慢性免疫介导疾病，影响估计 150 万美国人，并造成 150 万直接医疗费用。由于其发病年龄较轻且病程迁延且易复发，住院和手术给患者和社会造成了相当大的损失。随着抗肿瘤坏死因子α（抗- TNF）和抗整合素（维多珠单抗）疗法取得了持久的临床和疗效成果内镜下缓解的可能性越来越大，然而，五分之一的患者甚至无法实现。初始反应和每年相似比例的反应目前，治疗的选择是。基本上是非选择性的，对不同治疗类别的药物进行连续试验，无需经过然而，这会导致长期发病。疾病治疗不充分，增加了永久性肠道损伤的可能性因此，除了使患者接触无效但具有潜在毒性的药物外，还存在一种潜在的危险。对预测每种治疗类别反应的工具的重要未满足需求。吸烟、疾病持续时间、受累部位和行为等因素在我们之前的工作中，我们开发了一个预测治疗反应的方法。使用遗传风险等位基因来识别主要和次要无反应者的预测工具该工具证明了遗传学的实用性及其作为治疗方法的优越性。然而，这项工作的局限性包括回顾性。治疗反应类别的判定和对症状改善的依赖与内镜下炎症严重程度相关性较差，可以说是一个更强有力的标记。根据提案，我们的目标是在独立的前瞻性患者队列中验证我们的预测工具开始抗 TNF 治疗，对于评估其在确定反应方面的效用很重要粪便钙卫蛋白的变化和正常化，肠道敏感的客观标志物此外，我们的目标是开发有助于个性化精确治疗的工具。通过确定最有可能对每位患者有益的作用机制，我们将研究我们现有的治疗反应工具在前瞻性患者队列中的预测价值如果我们现有的模型无法预测对维多珠单抗的反应，我们将开发一个具有不同多态性的单独预测模型来预测对重要的是，该提案的见解将作为该治疗课程的基础。开发综合预测模型，该模型还包含成分和肠道微生物组的宏基因组功能将显着促进我们的目标这笔赠款还将为我们的患者提供个性化、精确的护理并确保最佳结果。提供重要的初步数据以支持申请人未来的独立R01资助提案，是申请人长期学术成功的至关重要的一步。