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，导致美国每年的医疗费用超过 1,420 亿美元。肠道纤维化推动了克罗恩病的手术需求，三分之二的患者需要进行手术。尽管这对美国医疗保健和克罗恩病患者产生了巨大影响，但我们还没有针对肠道纤维化的药物疗法。我们的初步数据表明，针对 Bcl-2 信号通路的小分子可以抑制肠道激活。该提案的目的是验证 Bcl-2 信号传导作为肠道纤维化的重要途径。该研究计划的长期目标是开发 Bcl-2 抑制剂，从而为肠道纤维化提供有效的药物治疗。克罗恩病。我们的初步数据表明，候选 Bcl-2 抑制剂可在体外和人肠道类器官中抑制人肠道肌成纤维细胞的活化，但这些化合物的效力有限，并且在小鼠体内存在全身暴露的潜在毒性。 Bcl-2 抑制剂 navitoclax 已被证明对人体是安全的，目前正处于癌症的 2 期临床试验中。我们建议改进现有化合物，以增强化合物的效力和肠道特异性，从而降低系统毒性。迭代开发和测试这些化合物的体外靶点特异性和抗纤维化活性的新颖性，将使用 TGFβ（细胞因子激活）和基质刚度在两个独立的肌成纤维细胞激活模型中显示。在目标 2 中，我们将通过评估肠道吸收以及血浆和肝微粒体中化合物的不稳定性来优化目标 1 中最有前途的 Bcl-2 抑制剂的药代动力学特性。最大耐受剂量的有前途的候选化合物，并在小鼠中进行 PK 和 PD 测试，将逐步测试这些化合物在两种啮齿动物模型（沙门氏菌）中的生物功效。鼠伤寒小鼠肠道纤维化模型和大鼠三硝基苯磺酸（TNBS）肠道纤维化模型所提出的研究具有创新性，因为它们将产生抑制新型抗纤维化途径的肠道选择性化合物，并严格测试两种中的最佳候选化合物。这项研究提案意义重大，因为它有可能通过验证器官纤维化的这一途径来影响患者护理，器官纤维化是克罗恩病和大多数形式的未满足的临床需求。慢性器官衰竭，包括肾衰竭和肝硬化。

项目成果

Management of Crohn Disease-Reply.

克罗恩病的管理-回复。

• 发表时间: 2021
• 作者: Cushing, Kelly;Higgins, Peter D R
• 通讯作者: Higgins, Peter D R

Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease.

通过基于 PCR 的粪便检测检测炎症性肠病患者肠道感染的患病率和影响。

• 发表时间: 2020-11
• 影响因子: 3.1
• 作者: Limsrivilai, Julajak;Saleh, Zachary M;Johnson, Laura A;Stidham, Ryan W;Waljee, Akbar K;Govani, Shail M;Gutermuth, Brian;Brown, Alexandra M;Briggs, Emily;Rao, Krishna;Higgins, Peter D R
• 通讯作者: Higgins, Peter D R

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。

• 发表时间: 2023-12-19
• 影响因子: 9.4
• 作者: Newman, Kira L;Higgins, Peter D R
• 通讯作者: Higgins, Peter D R

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

炎症性肠病肠纤维化的病理生理学、诊断和治疗面临的挑战。

• 发表时间: 2022-01
• 影响因子: 29.4
• 作者: D'Haens, Geert;Rieder, Florian;Feagan, Brian G;Higgins, Peter D R;Panés, Julian;Maaser, Christian;Rogler, Gerhard;Löwenberg, Mark;van der Voort, Robbert;Pinzani, Massimo;Peyrin;Danese, Silvio;International Organization for In
• 通讯作者: International Organization for In

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

托法替尼治疗具有生物制剂经验的急性严重溃疡性结肠炎住院患者：一项回顾性病例对照研究。

• 发表时间: 2021
• 作者: Berinstein, Jeffrey A;Sheehan, Jessica L;Dias, Michael;Berinstein, Elliot M;Steiner, Calen A;Johnson, Laura A;Regal, Randolph E;Allen, John I;Cushing, Kelly C;Stidham, Ryan W;Bishu, Shrinivas;Kinnucan, Jami A R;Cohen;Walj
• 通讯作者: Walj