IND enabling development of LGM2605 as adjuvant treatment for asthma

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。

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.