The Development of 4-methylumbelliferone Pro-drugs to Prevent Autoimmune Diabetes

预防自身免疫性糖尿病的 4-甲基伞形酮前药的开发

• 批准号: 9901521
• 负责人: Paul L Bollky
• 金额: $ 43.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901521
• 关键词: 4-methylumbelliferone; ADME Study; Adolescent; Adult; American; Animal Model; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Beta Cell; Biliary; Biological Availability; Blindness; Child; Clinical; Data; Deposition; Development; Diabetes Mellitus; Diabetes prevention; Dose; Drug Kinetics; Evaluation; Extracellular Matrix; FOXP3 gene; Foundations; Generations; Human; Hyaluronan; Immune response; Inbred NOD Mice; Individual; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Kidney Failure; Kinetics; Lead; Metabolism; Oral; Oral Administration; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Phenols; Phenotype; Polymers; Prevention; Preventive therapy; Prodrugs; Regimen; Regulatory T-Lymphocyte; Safety; Spasm; Stroke; Structure of beta Cell of islet; T-Lymphocyte; Tissues; Toxic effect; Vision; diabetes pathogenesis; disorder risk; dosage; improved; in vivo; inhibitor/antagonist; islet; mouse model; novel; preclinical study; prevent; prototype; sound

Project Summary Type 1 diabetes (T1D) is an autoimmune disease that destroys the pancreatic β cells that produce insulin. Over 30,000 Americans, mostly children and adolescents, will develop T1D this year. Many will go on to suffer blindness, kidney failure, and stroke as a result of their diabetes. While we can identify individuals at risk for the disease, currently there are no approved treatments that prevent T1D. We recently identified a novel target molecule that contributes to the development of T1D. Hyaluronan (HA) is an extracellular matrix (ECM) polymer that is abundant in islets under autoimmune attack. HA polarizes local immune responses towards a pro-inflammatory Th1 T-cell phenotype and prevents induction of pro- tolerogenic, Foxp3+ regulatory T-cells (Treg), thereby contributing to the pathogenesis of T1D. We have also identified a compound that may prevent T1D. 4-methylumbelliferone (4-MU) is an oral inhibitor of HA synthesis, which clears islet HA deposits and prevents diabetes in multiple animal models of T1D, including in DORmO and Non Obese Diabetic (NOD) mice. These effects are associated with an increase in pro-tolerogenic, Foxp3+ Tregs and prevention of β cell destruction. Our data suggest that it may be possible to prevent T1D in humans by targeting HA synthesis with 4-MU, our lead compound. These results are particularly exciting because 4-MU is already an approved drug. Called “hymecromone”, it has been prescribed for >40 years to treat biliary spasm. It is safe, well-tolerated, approved in children as well as adults, and could be an ideal oral agent to prevent progression to T1D. Unfortunately, 4-MU has poor pharmacokinetics that precludes its clinical use for T1D prevention. In particular, oral 4-MU has low bioavailability. Consequently, large doses of 4-MU are required in our animal models. Administration of comparable regimens is impractical in humans, such that it is not possible to repurpose 4-MU for human T1D prevention. We need an improved version of 4-MU with better bioavailability. A pro-drug strategy is often used to improve the bioavailability of phenolic compounds like 4-MU, our prototype lead compound. In proof of principle studies we have generated a 4-MU pro-drug which delays the onset of autoimmune diabetes, demonstrating that this approach is feasible and pharmacologically sound. Along with these efforts to improve upon the bioavailability of 4-MU, we also need to understand what tissue levels of 4-MU are required to effectively target islet HA synthesis. Further, we need to define the relationship between oral 4-MU dosage and islet 4-MU exposure. Here, we propose a systematic framework for the pharmacologic evaluation of 4-MU, for the generation of 4-MU pro-drugs, and for their functional assessment in well-validated and predictive animal models of autoimmune diabetes. Together, these early-stage, pre-clinical studies will establish the mechanistic and pharmacologic foundations necessary to for ADME studies in humans and a human phase I clinical trial.

项目摘要 1型糖尿病(T1D)是一种自身免疫性疾病，会破坏分泌胰岛素的胰腺β细胞。 今年将有超过30,000名美国人患上T1D，其中大部分是儿童和青少年。许多人将继续受苦 失明、肾功能衰竭和糖尿病导致的中风。虽然我们可以确定有风险的个人 这种疾病，目前还没有被批准的治疗方法来预防T1D。 我们最近发现了一个新的靶分子，它有助于T1D的发展。透明质酸(HA) 是一种细胞外基质(ECM)聚合物，在自身免疫攻击下丰富存在于胰岛中。房委会使当地两极分化 对促炎性Th1T细胞表型的免疫反应和防止诱导促炎性T细胞 产生耐受性的Foxp3+调节性T细胞(Treg)，从而参与T1D的发病。 我们还发现了一种可能预防T1D的化合物。4-甲基伞形酮(4-MU)是一种口服 HA合成抑制剂，清除胰岛HA沉积，预防糖尿病 T1D，包括在Dormo和非肥胖糖尿病(NOD)小鼠中。这些效果与 增加促耐受性、Foxp3+Treg和防止β细胞破坏。我们的数据表明，它可能是 我们的先导化合物4-MU可以通过靶向HA的合成来预防人类的T1D。 这些结果特别令人兴奋，因为4-MU已经是一种被批准的药物。名为“赞美诗”， 它已经被开了40年的处方来治疗胆管痉挛。它是安全的，耐受性良好，在儿童中被批准为 对于成年人来说也是如此，可能是防止进展为T1D的理想口服药物。 不幸的是，4-MU的药代动力学较差，不能用于预防T1D的临床应用。在……里面 特别是口服4-MU的生物利用度较低。因此，我们的动物需要大剂量的4-MU 模特们。在人类身上实施类似的治疗方案是不切实际的，因此不可能 将4-MU重新用于人类T1D预防。我们需要一个具有更好生物利用度的改进版本的4-MU。 亲药物策略经常被用来提高酚类化合物的生物利用度，如4-MU，我们的 原型铅化合物。在原理研究的证据中，我们已经产生了一种4-MU前药，它推迟了 自身免疫性糖尿病的发病，证明这种方法是可行的，药理上是合理的。 在努力提高4-MU的生物利用度的同时，我们还需要了解 组织水平的4-MU是有效靶向胰岛HA合成所必需的。此外，我们需要定义 口服4-MU剂量与胰岛4-MU暴露的关系 在这里，我们提出了一个系统的框架，为4-MU的药理评价，为产生 4-MU前体药物，以及它们在有效验证和预测的动物模型中的功能评估。 自身免疫性糖尿病。总之，这些早期的、临床前的研究将建立 人体ADME研究和人类I期临床试验所必需的药理学基础。