Inhibiting Bcl-2-regulated intestinal fibrosis in models of Crohn’s Disease

抑制克罗恩病模型中 Bcl-2 调节的肠道纤维化

• 批准号: 10417063
• 负责人: Peter D.R. Higgins
• 金额: $ 46.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417063
• 关键词: Affect; Anti-Inflammatory Agents; Apoptosis; Area; BCL2 gene; BCL2L1 gene; Basic Science; Biological Testing; Chronic; Chronic Disease; Cicatrix; Clinical; Congestive Heart Failure; Crohn' s disease; Cytokine Activation; Data; Development; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Excision; Family member; Fibroblasts; Fibrosis; Future; Gene Expression; Goals; Healthcare; Healthcare Systems; Heart; Human; In Vitro; Inflammation; Intestinal Fibrosis; Intestines; Kidney; Kidney Failure; Lead; Liver; Liver Cirrhosis; Liver Microsomes; Lung; MCL1 gene; Maximum Tolerated Dose; Mechanics; Mediator of activation protein; Medical; Medical Care Costs; Medicine; Modeling; Mus; Myofibroblast; Operative Surgical Procedures; Oral; Organ; Organ failure; Organoids; Pathway interactions; Patient Care; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Property; Pulmonary Fibrosis; Rattus; Research; Research Proposals; Resistance; Rodent Model; Salmonella typhimurium; Scleroderma; Signal Pathway; Signal Transduction; Solubility; Specificity; Sulfonic Acids; Surgical complication; Testing; Toxic effect; Transforming Growth Factor beta; Translating; Trinitrobenzenes; United States; Validation; Variant; absorption; base; cancer clinical trial; clinical development; cost; drug efficacy; effective therapy; efficacy testing; fibrogenesis; healing; improved; in vitro Model; in vitro testing; in vivo; inhibitor; innovation; molecular targeted therapies; mouse model; new therapeutic target; novel; pill; potency testing; pre-clinical; process optimization; programs; response; small molecule; small molecule inhibitor; success; systemic toxicity; therapeutic candidate

Fibrosis is the final common pathway to organ failure in many chronic diseases, leading to over $142 billion in annual medical costs in the United States. Intestinal fibrosis drives the need for surgery in Crohn's disease, which is required in two-thirds of all patients. Despite this immense impact on U.S. healthcare and patients with Crohn's disease, we have no medical therapies for intestinal fibrosis. Our preliminary data show that small molecules targeting the Bcl-2 signaling pathway can inhibit the activation of intestinal fibroblasts. The objective of this proposal is to validate Bcl-2 signaling as an important pathway for intestinal fibrosis. The long-term objective of this research program is to develop inhibitors of Bcl-2 that will lead to effective medical therapies for intestinal fibrosis in Crohn's disease. Our preliminary data demonstrate that candidate Bcl-2 inhibitors inhibit human intestinal myofibroblast activation in vitro and in human intestinal organoids. However, these compounds have limited potency, and potential toxicity from systemic exposure in mice. An existing Bcl-2 inhibitor, navitoclax, has been proven safe in humans and is now in phase 2 clinical trials for cancer. We propose to improve upon the current compounds to enhance compound potency and gut specificity to reduce systemic toxicity. In Aim 1, we will iteratively develop and test novel variants of these compounds for in vitro target specificity and anti-fibrotic activity. Potency will be shown in two independent models of myofibroblast activation, using TGFβ (cytokine activation) and matrix stiffness (mechanical activation). In Aim 2, we will optimize the pharmacokinetic properties of the most promising Bcl-2 inhibitors from Aim 1 by evaluating oral absorption into the gut and compound instability in plasma and liver microsomes. In Aim 3, we will determine the maximum tolerated dose of promising candidate compounds, and perform PK and PD testing in mice. Promising gut-selective compounds will progress to stepwise testing of the biologic efficacy of these compounds in two rodent models, the Salmonella typhimurium mouse model of intestinal fibrosis, and the rat trinitrobenzene sulfonic acid (TNBS) model of intestinal fibrosis. The proposed studies are innovative in that they will generate gut-selective compounds that inhibit a novel antifibrotic pathway, and rigorously test the best candidates in two rodent models. This research proposal is significant in that it has the potential to impact patient care by validating this pathway in organ fibrosis, a significant unmet clinical need in Crohn's disease and in most forms of chronic organ failure, including kidney failure and liver cirrhosis.

纤维化是许多慢性疾病导致器官衰竭的最终常见途径，在美国每年导致超过1420亿美元的医疗费用。肠纤维化促使克罗恩病需要手术治疗，三分之二的患者需要手术治疗。尽管这对美国的医疗保健和克罗恩病患者产生了巨大的影响，但我们还没有针对肠道纤维化的药物疗法。我们的初步数据显示，靶向Bcl-2信号通路的小分子可以抑制肠道成纤维细胞的激活。本研究的目的是验证Bcl2信号转导通路在肠纤维化中的作用。这项研究计划的长期目标是开发能有效治疗克罗恩病肠道纤维化的Bcl2抑制剂。我们的初步数据表明，候选的Bcl-2抑制剂在体外和在人肠器官中抑制人肠肌成纤维细胞的激活。然而，这些化合物的效力有限，而且对小鼠的全身暴露具有潜在的毒性。现有的一种Bcl-2抑制剂Navitoclax已被证明在人类身上是安全的，目前正处于癌症的第二阶段临床试验。我们建议在现有化合物的基础上进行改进，以提高化合物的效力和肠道特异性，以降低全身毒性。在目标1中，我们将反复开发和测试这些化合物的新变种，用于体外靶向特异性和抗纤维化活性。使用转化生长因子β(细胞因子激活)和基质僵硬(机械激活)两种独立的肌成纤维细胞激活模型将显示其效力。在目标2中，我们将通过评估口服吸收和血浆和肝脏微粒体中化合物的不稳定性来优化来自目标1的最有希望的Bcl-2抑制剂的药代动力学特性。在目标3中，我们将确定有希望的候选化合物的最大耐受量，并在小鼠身上进行PK和PD测试。有希望的肠道选择性化合物将在两个啮齿动物模型-鼠伤寒沙门氏菌肠纤维化模型和大鼠三硝基苯磺酸(TNBS)肠纤维化模型上逐步测试这些化合物的生物有效性。拟议的研究具有创新性，因为它们将产生肠道选择性化合物，抑制一种新的抗纤维化途径，并在两个啮齿动物模型中严格测试最佳候选者。这项研究建议具有重要意义，因为它有可能通过在器官纤维化中验证这一途径来影响患者的护理，器官纤维化是克罗恩病和大多数形式的慢性器官衰竭(包括肾功能衰竭和肝硬变)的重要临床需求。

项目成果

Challenges in the Pathophysiology, Diagnosis, and Management of Intestinal Fibrosis in Inflammatory Bowel Disease.

炎症性肠病中肠道纤维化的病理生理学，诊断和管理挑战。

• DOI: 10.1053/j.gastro.2019.05.072
• 发表时间: 2022-01
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: D'Haens G;Rieder F;Feagan BG;Higgins PDR;Panés J;Maaser C;Rogler G;Löwenberg M;van der Voort R;Pinzani M;Peyrin-Biroulet L;Danese S;International Organization for Inflammatory Bowel Disease Fibrosis Working Group
• 通讯作者: International Organization for Inflammatory Bowel Disease Fibrosis Working Group

Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study.

用于生物经验的急性严重溃疡性结肠炎患者的tofacitib：一项回顾性病例对照研究。

• DOI: 10.1016/j.cgh.2021.05.038
• 发表时间: 2021-10
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Berinstein JA;Sheehan JL;Dias M;Berinstein EM;Steiner CA;Johnson LA;Regal RE;Allen JI;Cushing KC;Stidham RW;Bishu S;Kinnucan JAR;Cohen-Mekelburg SA;Waljee AK;Higgins PDR
• 通讯作者: Higgins PDR

Risk Variants in or Near ZBTB40 AND NFATC1 Increase the Risk of Both IBD and Adverse Bone Health Outcomes Highlighting Common Genetic Underpinnings Across Both Diseases.

ZBTB40 和 NFATC1 中或附近的风险变异会增加 IBD 和不良骨骼健康结果的风险，凸显这两种疾病的共同遗传基础。

• DOI: 10.1093/ibd/izac273
• 发表时间: 2023
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Cushing,KellyC;Chen,Yanhua;Du,Xiaomeng;Chen,Vincent;Kuppa,Annapurna;Higgins,Peter;Speliotes,ElizabethK
• 通讯作者: Speliotes,ElizabethK

Fecal calprotectin level is nonlinearly associated with GI pathogen detection in patients with and without inflammatory bowel disease.

在患有或不患有炎症性肠病的患者中，粪便钙卫蛋白水平与胃肠道病原体检测呈非线性相关。

• DOI: 10.1128/jcm.00946-23
• 发表时间: 2023
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: Newman,KiraL;Higgins,PeterDR
• 通讯作者: Higgins,PeterDR

Management of Crohn Disease: A Review.

• DOI: 10.1001/jama.2020.18936
• 发表时间: 2021-01-05
• 期刊: JAMA