权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

IND enabling development of LGM2605 as adjuvant treatment for asthma

IND 使 LGM2605 能够开发为哮喘辅助治疗药物

基本信息

批准号：
10205985
负责人：
ANGELA HACZKU
金额：
$ 96.43万
依托单位：
LIGNAMED, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-18 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205985
关键词：
Adjuvant Adrenal Cortex Hormones Affect Aftercare Age Animals Anti-Inflammatory Agents Antioxidants Asthma Automobile Driving Biological Biological Assay Biological Availability Blood Bronchoalveolar Lavage Categories Cell Count Cell Culture Techniques Cell Line Cells Clinic Clinical Trials Collaborations Dendritic Cells Development Dexamethasone Dose Drug Kinetics Effectiveness Enrollment Epigenetic Process Epithelial Epithelial Cells Evaluation Flax Free Radical Scavenging Future Gender Gene Expression Genetic Transcription Glucocorticoid Receptor Glucocorticoids Human Immune Impairment In Vitro Inflammation Inhalation Isomerism Macaca Macaca mulatta Mainstreaming Modeling Molecular Mus Myelogenous NF-kappa B NR3C1 gene Optics Oral Ozone Pathway interactions Pennsylvania Peripheral Blood Mononuclear Cell Phase Phenotype Phylogenetic Analysis Predisposition Psychosocial Stress Pulmonary Surfactant-Associated Protein D Receptor Gene Regimen Regulation Reporting Resistance Role Sampling Small Business Technology Transfer Research Smooth Muscle Myocytes Steroid Resistance Stress Structure Symptoms Testing Universities airway epithelium airway hyperresponsiveness airway inflammation airway obstruction asthma exacerbation asthmatic asthmatic patient base biobank bronchial epithelium cell type cohort design enterodiol healthy volunteer immune activation improved in vitro activity in vivo inflammatory marker inhibitor/antagonist methacholine nonhuman primate novel nuclear factor-erythroid 2 ozone exposure prevent receptor expression receptor function research clinical testing respiratory smooth muscle response scale up secoisolariciresinol transcription factor transcriptome sequencing translational approach

项目摘要

Project summary IND enabling development of LGM2605 as adjuvant treatment for asthma Glucocorticoid resistance is a major treatment problem in asthma. Our recent studies in mice, non-human primates and severe asthma patients, along with reports by others suggest that glucocorticoid receptor (GR) expression was impaired by psychosocial stress, in association with enhanced NF-kB activation and glucocorticoid non-responsiveness of immune cells. This Phase II STTR proposal was developed jointly between LignaMed (Dr. Sielecki), UPenn (Dr. Christofidou-Solomidou and UC Davis (Dr. Haczku) based on our results generated by the Phase I STTR project. Our study strongly suggested that LGM2605, a racemic synthetic form of a novel, natural, non-toxic, anti-inflammatory component of flaxseed, secoisolariciresinol diglucoside (SDG) may be effective to treat severe asthma exacerbation induced by inhalation of ozone. LGM2605 is a racemate which has proven free radical scavenging activities in vitro and in vivo and it induces activation of nuclear factor erythroid 2-related factor 2 (NRF2) a major anti-oxidant transcription regulator and inhibitor of NF-kB. As part of assembling an IND package we will complete a pivotal proof of concept study using rhesus macaques, because of their phylogenetic proximity to humans with a high degree of immune crossreactivity and a predisposition to spontaneously develop both asthma and psychosocial stress. Our exciting preliminary results from stressed asthmatic macaques treated with LignaMed’s LGM2605 demonstrated a significant suppression of airway inflammation and it abolished airway hyperresponsiveness (AHR) in response to ozone exposure. We hypothesize that LGM2605 alleviates asthma symptoms by interfering with activation of immune and airway structural (epithelial and smooth muscle) cells and improving glucocorticoid responsiveness through activation of NRF2 gene expression and downstream anti-oxidant pathways. Aim 1. Assess the mechanism of action and dose-dependent effects of LGM2605 treatment on regulation of the GR, NF-kB and NRF2 expression and glucocorticoid responsiveness in vitro. Aim 2. A. Scale up and definition of release specifications of the single isomer of LGM2605; B. Pharmacokinetic evaluation of the single isomer of LGM2605 in non- human primates (rhesus macaques). Aim 3. Study the dose-dependent effects of single isomer LGM2605 on preventing AHR, immune cell activation and improving glucocorticoid responsiveness in ozone- exposed rhesus macaques. Our translational approach using rhesus macaques (in vivo clinical testing) and cells from severe asthma patients (in vitro mechanistic studies on cell types relevant to asthma) will establish how LGM2605 affects glucocorticoid responsiveness and will lay the groundwork for subsequent human clinical trials.

项目总结 IND开发LGM2605作为哮喘辅助治疗药物糖皮质激素抵抗是哮喘的主要治疗问题。我们最近对小鼠、非人类的研究灵长类动物和重症哮喘患者，以及其他人的报告表明，糖皮质激素受体(GR) 表达受到心理社会应激的损害，与增强的核因子-kB活性和免疫细胞对糖皮质激素无反应性。这项第二阶段STTR提案是由以下机构联合开发的 LignaMed(西莱茨基博士)，UPenn(Christofidou-Solomidou博士)和UC Davis(Haczku博士)基于我们的结果由STTR第一阶段项目生成。我们的研究强烈表明，LGM2605，一种外消旋合成形式亚麻籽中一种新的天然、无毒、抗炎成分--二异落叶松脂醇二葡萄糖苷(SDG) 可能对吸入臭氧引起的严重哮喘恶化有效。LGM2605是外消旋体已证实其在体内外具有清除自由基的活性，并能诱导核因子的激活红系2相关因子2(NRF2)是核因子-kB的主要抗氧化剂、转录调节因子和抑制因子。作为以下内容的一部分组装IND包后，我们将使用恒河猴完成一项关键的概念验证研究，因为它们与人类的亲缘关系具有高度的免疫交叉反应性和易感性会自发地发展为哮喘和社会心理压力。我们令人兴奋的初步结果来自于压力 LignaMed公司的LGM2605治疗哮喘猕猴显示出显著的呼吸道抑制炎症和它消除了对臭氧暴露的呼吸道高反应性(AHR)。我们假设LGM2605通过干扰免疫和呼吸道的激活来缓解哮喘症状结构(上皮和平滑肌)细胞与通过激活提高糖皮质激素反应性 NRF2基因表达与下游抗氧化通路的关系。目标1.评估行动机制 LGM2605对糖皮质激素受体、核因子-kB和NRF2表达的调节作用体外对糖皮质激素的反应性。目标2.版本规范的扩展和定义 LGM2605单一异构体的药代动力学研究人类灵长类动物(猕猴)。目的3.研究单一异构体LGM2605的量效关系关于臭氧中预防AHR、免疫细胞激活和提高糖皮质激素反应性的研究裸露的恒河猴。我们使用恒河猴的翻译方法(活体临床测试)和重症哮喘患者的细胞(与哮喘相关的细胞类型的体外机制研究)将建立 LGM2605如何影响糖皮质激素的反应性，并将为后续的人类临床奠定基础审判。