Targeting POGLUT1 to promote biliary development in Alagille syndrome

靶向 POGLUT1 促进 Alagille 综合征胆道发育

• 批准号: 10449607
• 负责人: Stacey S Huppert
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449607
• 关键词: Address; Adverse effects; Affect; Age; Alagille Syndrome; Antisense Oligonucleotides; Area; Bile Acids; Bile Duct Diseases; Bile fluid; Biliary; Binding; Bypass; Cardiovascular system; Characteristics; Child; Childhood; Cholestasis; Clinical; Clinical Research; Collaborations; Data; Development; Disease; Foundations; Frequencies; Genes; Genetic; Genetic Models; Goals; Government; Hepatocyte; Heterozygote; Immune; Industry; Intrahepatic bile duct; Kidney; Knowledge; Lead; Ligands; Liver; Liver diseases; Long-Term Effects; Mediating; Medical; Modeling; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Notch Signaling Pathway; Operative Surgical Procedures; Organ; Organ Donor; Other Genetics; Pathway interactions; Patients; Persons; Pharmacologic Substance; Phenotype; Plant Resins; Portal vein structure; Pruritus; Publishing; Regulation; Reporting; Research; Severities; System; Therapeutic; Therapeutic immunosuppression; Time; Transplantation; Treatment Efficacy; Waiting Lists; Work; autosomal dominant mutation; base; bile duct; biliary tract; body system; cell type; clinical care; developmental disease; dosage; end stage liver disease; glycosyltransferase; improved; industry partner; inhibitor; intrahepatic; knock-down; liver injury; liver transplantation; mouse model; notch protein; novel strategies; novel therapeutic intervention; patient population; postnatal; preclinical study; ranpirnase; side effect; targeted treatment; therapy development; transcription factor; transplantation therapy; treatment strategy

PROJECT SUMMARY/ABSTRACT Alagille syndrome (ALGS) is a genetic, multisystem developmental disorder affecting the liver biliary system, cardiovascular system, kidney and other organs. The most common phenotype observed in ALGS patients is a severe decrease in the number of bile ducts in the liver (called bile duct paucity). Similar to other diseases involving intrahepatic biliary system, bile duct paucity and its consequences often lead to cholestatic phenotypes (like severe itching) and end-stage liver disease in ALGS patients. Dominant mutations in a gene called JAG1, which encodes a ligand in the Notch signaling pathway, were identified as the cause of ALGS in 1997, and were later shown to be responsible for about 95% of ALGS cases. However, despite the wealth of knowledge on the function and regulation of Notch pathway and despite the passage of more than 2 decades from the discovery of JAG1 in ALGS patients, there is still no mechanism-based therapy for this disease. The only cure for ALGS liver disease and diseases of bile duct paucity is liver transplantation. However, the shortage in liver donor poses a significant challenge to this patient population. Moreover, involvement of other organ systems—including the cardiovascular and renal systems—in many ALGS patients makes them poor candidates for liver transplantation. Moreover, for those who do receive a liver transplant, a higher frequency of cardiovascular and kidney complications are observed, and the long-term effects of immunosuppressive therapy can be problematic. Therefore, development of therapies that can correct or decrease the degree of bile duct paucity and help avoid or delay transplant is a major unmet clinical/medical need of patients with ALGS and other diseases with bile duct paucity. Building on our recently published and preliminary data, the current application proposes preclinical studies to directly address this need. We have established a mouse model for ALGS by removing one copy of Jag1 on a C57BL/6 genetic background. This model allowed us to identify two dosage-sensitive genetic modifiers of the Jag1 heterozygosity in the liver, which can rescue the bile duct paucity and liver phenotypes without causing side effects. Moreover, our preliminary data generated in collaboration with an industry partner indicate that postnatal reduction in the expression of one of these modifiers by a novel approach can significantly improve the liver phenotypes in our ALGS mouse model. In the two Aims of this proposal, we will determine the optimal dosage, long-term benefits, and the potential side effects of our treatment strategy in Jag1 heterozygous and other genetic models of ALGS with more severe liver involvement and/or multiple organ involvement. If successful, our research will establish a strategy for augmentation of the biliary tree in bile duct paucity models and will pave the way for clinical studies which might one day help ALGS patients avoid liver transplantation.

项目总结/摘要 Alagille综合征（ALGS）是一种影响肝胆系统的遗传性多系统发育障碍， 心血管系统、肾脏和其他器官。在ALGS患者中观察到的最常见的表型是 肝脏中胆管数量严重减少（称为胆管缺乏）。与其他疾病相似 累及肝内胆管系统，胆管缺如及其后果常导致胆汁淤积 表型（如严重瘙痒）和ALGS患者的终末期肝病。基因显性突变 称为JAG 1，编码Notch信号通路中的配体，被鉴定为ALGS的原因， 1997年，后来被证明是负责约95%的ALGS案件。然而，尽管财富 Notch通路的功能和调节的知识，尽管过去了20多年， 从在ALGS患者中发现JAG 1开始，对于这种疾病仍然没有基于机制的治疗。的 ALGS肝病和胆管缺乏性疾病的唯一治疗方法是肝移植。但 肝脏供体短缺对这一患者群体构成了重大挑战。此外，其他参与 器官系统-包括心血管和肾脏系统-在许多ALGS患者使他们贫穷 肝移植的候选人此外，对于那些接受肝移植的人来说， 观察心血管和肾脏并发症，免疫抑制剂的长期作用 治疗是有问题的因此，开发可以纠正或降低 胆管缺乏和帮助避免或延迟移植是患有肝硬化的患者的主要未满足的临床/医疗需求。 ALGS和其他胆管缺如的疾病。根据我们最近公布的初步数据， 本申请提出了临床前研究以直接解决这一需要。我们已经建立了一种小鼠 通过在C57 BL/6遗传背景上去除一个Jag 1拷贝来建立ALGS模型。这种模式使我们能够 确定两个剂量敏感的遗传修饰剂的Jag 1杂合性在肝脏中，这可以挽救 胆管缺乏和肝脏表型而不引起副作用。此外，我们的初步数据显示， 与一个工业伙伴合作，表明这些基因之一在出生后表达减少 通过一种新的方法修饰可以显着改善我们的ALGS小鼠模型的肝脏表型。在 本建议的两个目的，我们将确定最佳剂量，长期利益，和潜在的一方 我们的治疗策略在Jag 1杂合子和其他ALGS遗传模型中的作用， 肝脏受累和/或多器官受累。如果成功，我们的研究将建立一个战略， 在胆管缺乏模型中增加胆管树，并将为临床研究铺平道路， 也许有一天能帮助ALGS患者避免肝移植。