New Therapy for the Treatment of Primary Biliary Cholangitis.

治疗原发性胆汁性胆管炎的新疗法。

• 批准号: 10697484
• 负责人: MERRILL E GERSHWIN
• 金额: $ 44.81万
• 依托单位: EPIGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697484
• 关键词: Abdominal Pain; Acids; Acute; Affect; Arthritis; Autoimmune; Bile fluid; Body Weight decreased; Businesses; California; Cholangitis; Cholestasis; Chronic; Chronic Disease; Cicatrix; Cirrhosis; Clinical; Coupled; Data; Desire for food; Development; Disease; Disease Management; Disease Progression; Disease model; Dose; Enzymes; Female; Fibrosis; Foundations; Future; GTP-Binding Proteins; Hepatotoxicity; Human; IL17 gene; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Lead; Link; Liver; Liver Failure; Liver diseases; Lysophosphatidic Acid Receptors; Marketing; Medical; Medicine; Mitogens; Modeling; Mus; Neurons; Oral; Organ; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phase; Phenotype; Plasma; Population; Pre-Clinical Model; Primary biliary cirrhosis; Primates; Production; Pruritus; Quality of life; Risk; Role; Safety; Signaling Molecule; Skin; Symptoms; TNF gene; Therapeutic; Time; Tissues; Toxicology; Transforming Growth Factor beta; Universities; Ursodeoxycholic Acid; Woman; antagonist; appetite loss; associated symptom; bile duct; connective tissue growth factor; effective therapy; epigen; improved; in vitro activity; in vivo; inflammatory modulation; injured; innovation; liver injury; liver transplantation; lysophosphatidic acid; member; mouse model; novel; novel therapeutics; preclinical efficacy; receptor; response; screening; small molecule

Project Summary Primary biliary cholangitis (PBC) is a chronic disease in which the small bile ducts in the liver become injured and inflamed and eventually destroyed. When bile ducts are depleted, the resulting bile build up results in liver damage, leading to scarring, cirrhosis, and eventually liver failure. Among the common early symptoms of PBC is itchy skin (pruritus), tiredness, abdominal pain, low appetite, weight loss and arthritis. This chronic cholestatic liver disease predominantly affects women in their fourth and sixth decades. Currently therapeutic options to treat PBC are limited and much of the pharmacotherapy is restricted to management of disease symptomology. Lysophosphatidic acid (LPA) acts as a potent signaling molecule with wide-ranging effects on many different target tissues, and is implicated as a mitogen acting mainly through LPAR1 in the development of fibrosis in various organs. LPAR1 is also implicated in the development of arthritis. Many of these observed effects appear to involve LPAR1 activation and modulation of inflammatory responses through numerous signaling molecules including TNFα, IFNγ, IL-17, CTGF and TGFβ. IFNγ and IL-17 are signaling molecules implicated in the development of PBC. Pruritus is a serious symptom associated with PBC which has been linked to Autotaxin, the enzyme responsible for plasma LPA production. LPA may act on neurons through its receptors of which LPAR1 is the principal receptor expressed. Thus, LPAR1 may represent a key locus in the development of both pathologic inflammation and serious quality of life symptoms. Epigen has identified several classes of potent and selective LPAR1 antagonists from which an initial lead compound EPGN696 and backup EPGN2154 have demonstrated pre-clinical efficacy in other disease models. These compounds do not show cholestatic risk in human cellular hepato-toxicity models compared to a clinical compound BMS-986020 which has been withdrawn. We propose to profile the two LPAR1 antagonists for utility in PBC for their ability to modulate key inflammatory signaling molecules IFNγ and IL-17 and itch responses in pre-clinical models. Completion of lead profiling will result in selection of a single lead that will be evaluated in a pre-clinical model of PBC, conducted at University of California Davis. These studies will determine the feasibility of developing a LPAR1 antagonist for treatment of PBC.

项目概要 原发性胆汁性胆管炎 (PBC) 是一种肝脏小胆管受损的慢性疾病 当胆管耗尽时，就会发炎并最终被破坏，由此产生的胆汁积聚导致肝脏。 损害，导致疤痕、肝硬化，并最终导致肝功能衰竭，这是 PBC 常见的早期症状。 是皮肤发痒（瘙痒）、疲倦、腹痛、食欲不振、体重减轻和关节炎这种慢性疾病。 胆汁淤积性肝病主要影响四六十岁的女性，目前正在接受治疗。 治疗 PBC 的选择有限，并且大部分药物疗法仅限于疾病管理 症状学。 溶血磷脂酸 (LPA) 作为一种有效的信号分子，对许多疾病具有广泛的影响 不同的靶组织，并且作为有丝分裂原主要通过 LPAR1 在细胞发育过程中发挥作用。 LPAR1 也与许多关节炎的发展有关。 影响似乎涉及 LPAR1 的激活和通过多种方式调节炎症反应。 信号分子包括TNFα、IFNγ、IL-17、CTGF以及IFNγ和IL-17。 瘙痒是与 PBC 相关的严重症状，已被证实与 PBC 的发生有关。 与 Autotaxin 相关，负责血浆 LPA 产生的酶可能通过其作用于神经元。 LPAR1 是其表达的主要受体，因此，LPAR1 可能是该受体中的一个关键位点。 病理性炎症和严重的生活质量症状的发展。 Epigen 已鉴定出几类有效且选择性的 LPAR1 拮抗剂，其中初步 先导化合物 EPGN696 和备用 EPGN2154 已在其他疾病中证明了临床前疗效 与其他化合物相比，这些化合物在人类细胞肝毒性模型中没有表现出胆汁淤积风险。 临床化合物 BMS-986020 已被撤回，我们建议对两个 LPAR1 进行分析。 拮抗剂在 PBC 中发挥作用，因为它们能够调节关键炎症信号分子 IFNγ 和 IL-17 和临床前模型中的瘙痒反应。 完成先导分析后，将选择一个单一先导，并在临床前评估中进行评估 加州大学戴维斯分校进行的 PBC 模型将确定其可行性。 开发 LPAR1 拮抗剂来治疗 PBC。