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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