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（T1 D）是一种自身免疫性疾病，破坏产生胰岛素的胰腺β细胞。 超过30，000名美国人，主要是儿童和青少年，今年将发展T1 D。很多人会继续受苦 失明，肾衰竭，以及因糖尿病导致的中风。虽然我们可以识别出有风险的个体， 这种疾病，目前还没有批准的治疗方法可以预防T1 D。 我们最近发现了一种新的靶分子，有助于T1 D的发展。透明质酸（HA） 是细胞外基质（ECM）聚合物，其在自身免疫攻击下在胰岛中丰富。HA使局部极化 针对促炎性Th 1 T细胞表型的免疫应答，并阻止促炎性Th 1 T细胞表型的诱导。 致耐受性Foxp 3+调节性T细胞（Treg），从而促进T1 D的发病机制。 我们还发现了一种可以预防T1 D的化合物。4-甲基伞形酮（4-MU）是一种口服 HA合成的抑制剂，其在多种动物模型中清除胰岛HA沉积并预防糖尿病， T1 D，包括DORmO和非肥胖糖尿病（NOD）小鼠。这些影响与 促耐受原性、Foxp 3 + T细胞的增加和β细胞破坏的预防。我们的数据表明 通过用我们的先导化合物4-MU靶向HA合成来预防人类T1 D。 这些结果特别令人兴奋，因为4-MU已经是一种批准的药物。叫做羟甲香豆素 它已被用于治疗胆痉挛超过40年。它是安全的，耐受性良好，在儿童中被批准为 以及成人，可能是一种理想的口服药物，以防止进展为T1 D。 不幸的是，4-MU具有较差的药代动力学，这排除了其用于T1 D预防的临床用途。在 特别地，口服4-MU具有低生物利用度。因此，我们的动物需要大剂量的4-MU 模型类似方案的施用在人类中是不切实际的，使得不可能在人类中施用类似方案。 将4-MU用于人类T1 D预防。我们需要一种具有更好生物利用度的4-MU的改进版本。 前体药物策略通常用于改善酚类化合物如4-MU的生物利用度，我们的研究表明， 原型铅化合物。在原理研究的证明中，我们已经产生了一种4-MU前药， 自身免疫性糖尿病的发病，证明这种方法是可行的和可靠的。 沿着这些提高4-MU生物利用度的努力，我们还需要了解 需要组织水平的4-MU以有效靶向胰岛HA合成。此外，我们需要定义 口服4-MU剂量与胰岛4-MU暴露之间的关系。 在这里，我们提出了一个系统的框架，用于4-MU的药理学评价， 4-MU前体药物，以及它们在充分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，这些早期临床前研究将建立机制， 这是人体ADME研究和人体I期临床试验所必需的药理学基础。