N-acetylglucosamine analogs for the treatment of Multiple Sclerosis.

N-乙酰氨基葡萄糖类似物用于治疗多发性硬化症。

基本信息

批准号：
8648546
负责人：
ANI OGANESYAN
金额：
$ 30万
依托单位：
GLIXIS THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-12 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648546
关键词：
Acetylglucosamine Address Adverse effects Anabolism Animals Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving Back Biological Cell Membrane Permeability Cell physiology Cell surface Cells Child Cholecalciferol Complex Cues Cytoplasm Data Development Disease Drug Kinetics Effectiveness Endocytosis Environmental Risk Factor Enzymes Future Genetic Genetic Code Genetic Risk Glycoproteins Goals Golgi Apparatus Growth Inhibitors Human Hyperactive behavior Immunosuppression In Vitro Inflammatory Inflammatory Bowel Diseases Injectable Mediating Metabolic Metabolism Molecular Molecular Genetics Multiple Sclerosis Mus Mutation Neuraxis Oral Pathogenesis Pathway interactions Phase Phase I Clinical Trials Polysaccharides Proteins Publishing Reporting Resistance Role Self Tolerance Signal Transduction Supplementation Surface T cell response T-Cell Receptor T-Lymphocyte Therapeutic Toxicology Treatment Efficacy analog cell growth cost disorder risk drug development genetic risk factor genetic variant glycosylation improved in vivo mouse model novel prevent public health relevance receptor sugar trait treatment strategy

项目摘要

Abstract Multiple sclerosis (MS) is a T-cell mediated autoimmune disorder of the central nervous system. Current treatment strategies for MS are predominated by injectable therapies that do not target an underlying cause of the disease, have modest efficacy and have high cost and/or side effects that limit tolerability and compliance. An oral therapy that promotes self-tolerance by targeting an underlying disease mechanism, rather than broad and nonspecific immunosuppression, remains a major unmet need for the management of MS. As a complex trait disease, multiple genetic and environmental factors combine to influence disease risk in MS. Our published data in both mice and humans indicates that multiple genetic and environmental risk factors for MS converge to dysregulate protein N-glycosylation, thereby driving pathogenic autoimmune T cell responses. Therapeutic supplementation to N-glycan biosynthesis may provide the first therapy directly targeting an underlying cause of the disease. Indeed, supplementing the Golgi with the simple sugar N- acetylglucosamine (GlcNAc) rescues N-glycan branching deficiency in T cells by increasing metabolic supply of substrate to the Golgi enzymes, suppresses T cell growth and autoimmune T cell responses, prevents and treats mouse models of MS and/or autoimmune diabetes and improved disease in 8 of 12 human children with treatment-resistant inflammatory bowel disease. However, as a drug development target, GlcNAc has significant limitations. GlcNAc has poor membrane permeability, requiring high concentrations (40-80mM in vitro) for biological effects. To address this issue, we have developed novel analogs of GlcNAc that increase membrane permeability yet are converted back to GlcNAc by endogenous enzymes after entry into the cytoplasm. In preliminary studies, we have identified GlcNAc analogs that are effective at ~40,000 fold lower concentrations than GlcNAc in vitro, yet increase N-glycan branching with ~2 fold greater magnitude. The proposed project will examine differentially modified GlcNAc derivatives, for increased biological activity and efficacy in vitro and therapeutic efficacy in vivo. Specific Aim 1 will investigate GlcNAc analogs for optimal enhancement of N-glycan branching in vitro in mouse and human T cells. Specific Aim 2 will investigate GlcNAc analogs for suppression of mouse and human pro-inflammatory and autoimmune T cell responses in vitro. Specific Aim 3 will investigate oral delivery of GlcNAc analogs in mice that best increase N-glycan branching to suppress autoimmune T cell responses and treat mouse models of MS. In a future Phase II proposal, the single best analog will be targeted for development, including detailed in vivo toxicology and pharmacokinetic studies leading to a Phase 1 clinical trial. Our goal is to develop the first oral therapeutic that directly targets an underlying molecular and genetic defect that promotes autoimmune pathogenesis in MS.

抽象的多发性硬化症（MS）是中枢神经系统的T细胞介导的自身免疫性疾病。当前的MS治疗策略主要由不针对基础的注射疗法主导疾病的原因，具有适度的功效，具有较高的成本和/或副作用，可限制耐受性和遵守。通过针对潜在疾病机制来促进自我耐受的口服疗法，而不是广泛和非特异性免疫抑制，而是对管理的主要需求多发性硬化症。作为一种复杂的性状疾病，多种遗传和环境因素结合了影响疾病的风险多发性硬化症。我们在小鼠和人类中发表的数据表明，多种遗传和环境风险因素对于MS收敛到失调的蛋白质N-糖基化，从而驱动致病性自身免疫T细胞回答。补充N-聚糖生物合成的治疗性可以直接提供第一种疗法针对疾病的根本原因。确实，用简单的糖n-补充高尔基乙酰葡萄糖（GLCNAC）通过增加代谢供应来挽救T细胞中N-聚糖分支缺陷高尔基酶的底物，抑制T细胞的生长和自身免疫性T细胞反应，预防和治疗MS和/或自身免疫性糖尿病的小鼠模型，并改善了12名人类的疾病耐药性炎症性肠病。但是，作为药物开发目标，GlcNAC具有重大限制。 GlcNAC的膜渗透性较差，需要高浓度（40-80mm英寸体外）用于生物学作用。为了解决这个问题，我们开发了增加GlcNAC的新型类似物膜通透性却被内源性酶转化回GlcNAC，进入该酶细胞质。在初步研究中，我们已经确定了在低约40,000倍的GlcNAC类似物浓度比GlcNAC在体外，但增加了n-glycan分支，幅度更高。这拟议的项目将检查差异修饰的GlcNAC衍生物，以增加生物学活性和体内的体外和治疗功效。特定的目标1将研究GLCNAC类似物的最佳在小鼠和人T细胞中体外N-聚糖分支的增强。具体目标2将调查 GlcNAC类似物，用于抑制小鼠和人类促炎和自身免疫T细胞反应体外。具体目标3将调查最能增加N-聚糖的小鼠中GlcNAC类似物的口服输送分支以抑制自身免疫性T细胞反应并处理MS的小鼠模型。在未来的第二阶段提案，单一的最佳模拟将被针对开发，包括详细的体内毒理学和药代动力学研究导致1期临床试验。我们的目标是开发第一种口服治疗方法直接靶向促进MS自身免疫发病机理的潜在分子和遗传缺陷。