IND enabling development of LGM2605 as adjuvant treatment for asthma

项目摘要 IND使LGM 2605能够作为哮喘辅助治疗的开发成为可能 糖皮质激素抵抗是哮喘治疗的主要问题。我们最近在老鼠身上的研究， 沿着其他研究表明，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NF-κ B活化有关， 免疫细胞的糖皮质激素无反应性。第二阶段STTR提案由以下各方共同制定： 根据我们的结果，LignaMed（Sielecki博士）、宾夕法尼亚大学（Christofidou-Solomidou博士）和加州大学戴维斯分校（Haczku博士） 由一期STTR项目产生。我们的研究强烈表明，LGM 2605，一种外消旋合成形式， 亚麻籽的一种新的、天然的、无毒的抗炎成分，开环异落叶松树脂酚二葡萄糖苷（SDG） 可有效治疗由吸入臭氧引起的严重哮喘恶化。LGM 2605是一种 其已在体外和体内证明具有自由基清除活性， 红细胞2相关因子2（NRF 2）是一种主要的抗氧化转录调节因子和NF-kB抑制因子。的一部分 组装IND包，我们将使用恒河猴完成关键的概念验证研究，因为 它们与人类的亲缘关系很近，具有高度的免疫交叉反应性， 自发地发展哮喘和心理社会压力。我们的令人兴奋的初步结果， 用LignaMed的LGM 2605治疗的哮喘猕猴显示出显著的气道抑制， 炎症和它消除气道高反应性（AHR）在响应臭氧暴露。我们 假设LGM 2605通过干扰免疫和气道激活来减轻哮喘症状 结构（上皮和平滑肌）细胞和通过活化改善糖皮质激素反应性 NRF 2基因表达和下游抗氧化途径。目标1。评估作用机制 LGM 2605处理对GR、NF-kB和NRF 2表达的调节具有剂量依赖性作用 和体外糖皮质激素反应性。目标2. A.规模扩大和放行质量标准的定义 LGM 2605的单一异构体; B. LGM 2605单一异构体在非受试者中的药代动力学评价 人类灵长类动物（恒河猴）。目标3。研究单一异构体LGM 2605的剂量依赖性效应 防止AHR，免疫细胞活化和改善臭氧中糖皮质激素的反应性- 暴露的恒河猴。我们使用恒河猴的翻译方法（体内临床试验）和 来自严重哮喘患者的细胞（与哮喘相关的细胞类型的体外机制研究）将建立 LGM 2605如何影响糖皮质激素的反应性，并将为后续的人类临床研究奠定基础。 审判

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.