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.