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.

项目概要/摘要 阿拉吉尔综合征 (ALGS) 是一种影响肝胆系统的遗传性多系统发育障碍， ALGS 患者中观察到的最常见表型是心血管系统、肾脏和其他器官。 肝脏胆管数量严重减少（称为胆管缺乏），与其他疾病类似。 肝内胆管系统、胆管缺乏及其后果往往涉及导致胆汁淤积 ALGS 患者的表型（如严重瘙痒）和终末期肝病基因显性突变。 JAG1 编码 Notch 信号通路中的配体，被确定为 ALGS 的病因 1997 年，后来被证明是 95% 的 ALGS 病例的罪魁祸首。 尽管已经过去了 20 多年，但对 Notch 通路的功能和调节的了解 从ALGS患者中JAG1的发现来看，该病目前还没有基于机制的治疗方法。 ALGS 肝病和胆管缺乏症的唯一治疗方法是移植肝。 肝脏捐献者的短缺给这一患者群体带来了重大挑战。 许多 ALGS 患者的器官系统（包括心血管和肾脏系统）使他们变得贫穷 此外，对于那些接受肝移植的人来说，接受肝移植的频率更高。 观察心血管和肾脏并发症，以及免疫抑制剂的长期影响 因此，开发可以纠正或降低程度的疗法。 胆管缺乏并帮助避免或延迟移植是患有以下疾病的患者未满足的主要临床/医疗需求 根据我们最近发布的初步数据，ALGS 和其他胆管缺乏疾病。 目前的申请提出了临床前研究来直接解决这一需求，我们已经建立了一种小鼠。 通过在 C57BL/6 遗传背景上删除 Jag1 的一个副本，我们建立了 ALGS 模型。 鉴定出肝脏中 Jag1 杂合性的两个剂量敏感遗传修饰剂，这可以挽救 胆管缺乏和肝脏表型不会引起副作用此外，我们生成的初步数据。 与行业合作伙伴合作表明，产后其中一种基因的表达减少 通过一种新方法进行修饰可以显着改善我们的 ALGS 小鼠模型的肝脏表型。 该提案的两个目的是，我们将确定最佳剂量、长期效益和潜在方面 我们的治疗策略对 Jag1 杂合子和其他更严重的 ALGS 遗传模型的影响 如果成功，我们的研究将制定肝脏受累和/或多器官受累的策略。 在胆管缺乏模型中增强胆管树，将为临床研究铺平道路 也许有一天可以帮助 ALGS 患者避免肝移植。