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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 1 型糖尿病 (T1D) 是一种自身免疫性疾病，会破坏产生胰岛素的胰腺 β 细胞。今年将有超过 30,000 名美国人（其中大部分是儿童和青少年）患上 T1D，其中许多人将继续受苦。糖尿病导致失明、肾衰竭和中风，而我们可以识别出有患糖尿病风险的人。目前还没有批准的治疗方法可以预防 T1D。我们最近发现了一种有助于 T1D 发展的新型靶分子。是一种细胞外基质 (ECM) 聚合物，在自身免疫攻击下的胰岛中含量丰富，HA 会局部极化。针对促炎性 Th1 T 细胞表型的免疫反应，并防止诱导促炎性 Th1 T 细胞表型耐受性 Foxp3+ 调节性 T 细胞 (Treg)，从而促进 T1D 的发病机制。我们还发现了一种可以预防 T1D 的化合物，它是一种口服药物。 HA 合成抑制剂，可清除胰岛 HA 沉积物并预防多种动物模型中的糖尿病 T1D，包括 DORmO 和非肥胖糖尿病 (NOD) 小鼠，这些影响与促耐受性、Foxp3+ Tregs 的增加和预防 β 细胞破坏。通过使用我们的先导化合物 4-MU 靶向 HA 合成，可以预防人类 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，称为“hymecromone”。它已被用于治疗胆道痉挛超过 40 年。它是安全的，耐受性良好，被批准用于儿童。效果良好，并且可能是预防 1 型糖尿病进展的理想口服药物。不幸的是，4-MU 的药代动力学较差，阻碍了其用于预防 T1D 的临床应用。特别是，经测试，口服 4-MU 的生物利用度较低，我们的动物需要大剂量的 4-MU。类似的治疗方案在人类中的施用是不切实际的，因此不可能将 4-MU 用于人类 T1D 预防我们需要具有更好生物利用度的改进版本 4-MU。前药策略通常用于提高酚类化合物的生物利用度，例如 4-MU，我们的在研究原理证明中，我们生成了一种 4-MU 前药，可以延迟作用。自身免疫性糖尿病的发生，证明这种方法是可行的并且药理学上是合理的。除了这些提高 4-MU 生物利用度的努力之外，我们还需要了解什么有效靶向胰岛 HA 合成需要 4-MU 的组织水平。此外，我们需要定义 4-MU 的组织水平。口服 4-MU 剂量与胰岛 4-MU 暴露之间的关系。在这里，我们提出了一个用于 4-MU 药理学评价的系统框架，用于生成 4-MU 前药，及其在经过充分验证和预测的动物模型中的功能评估这些早期临床前研究将共同确定自身免疫性糖尿病的机制和机制。人体 ADME 研究和人体 I 期临床试验所需的药理学基础。