Developing non-anticoagulant recombinant heparin for treating the COPD Pathogenic Triad

项目摘要 该提案描述了一种治疗COPD（慢性阻塞性肺疾病）肺气肿的新策略 疾病），使用由基因工程哺乳动物细胞产生的独特定制的硫酸乙酰肝素。 肺气肿是慢性阻塞性肺病的主要组成部分，慢性阻塞性肺病是一种折磨高达5%的人口的疾病， 是美国的主要死亡原因。目前还没有一种药物已被证明有效治愈或延迟 疾病的进展。虽然靶向治疗几乎没有显示出临床益处，但肝素具有多点作用， 对疾病进展的三个主要驱动因素（蛋白酶、氧化应激和 炎症），并且可以吸入用于局部治疗。肝素的作用受到其抗凝剂的限制 活动TEGA Therapeutics的重组硫酸乙酰肝素生产技术可实现靶向消除 3-O-硫酸基团，是必不可少的抗凝活性，同时保持抗弹性蛋白溶解，抗 氧化和抗炎特性。产生硫酸乙酰肝素而不含3-O-的哺乳动物细胞系 硫酸盐将被基因工程化以改善对肺气肿驱动因子的抑制。产品将在 测试以评估它们在体外抑制蛋白酶、氧化应激和炎症介质的能力。最后， 通过在肺气肿大鼠模型中经口气管递送来评估最佳候选物的功效。 所得产品将在第二阶段通过生物工艺进一步开发为可吸入药物 开发、制剂、毒理学研究和药代动力学研究。这一奋进的成功将产生 一种临床药物，可限制肺气肿的进展，并增加持续时间和生活质量， 患者它可能也适用于其他慢性肺部疾病，包括囊性纤维化和α- 1例抗胰蛋白酶缺乏。

PROJECT SUMMARY This proposal describes a novel strategy to treat emphysema in COPD (chronic obstructive pulmonary disease) using uniquely tailored heparan sulfate produced from genetically engineered mammalian cells. Emphysema is a major component of COPD, a disease that afflicts up to 5% of the population and is the 4th leading cause of death in the US. There is currently no drug that has proven efficacious to cure or delay progression of the disease. While targeted therapies have shown little clinical benefit, heparin has multi-point inhibitory activity against the three major drivers of disease progression (proteases, oxidative stress and inflammation) and can be inhaled for local treatment. Heparin’s usefulness is limited by its anticoagulant activity. TEGA Therapeutics’ recombinant heparan sulfate production technology enables targeted elimination of 3-O-sulfate groups that are essential for anticoagulant activity while maintaining anti-elastolytic, anti- oxidative and anti-inflammatory properties. Mammalian cell lines that produce heparan sulfate without 3-O- sulfate will be genetically engineered to improve inhibition of emphysema drivers. The products will then be tested to evaluate their ability to inhibit proteases, oxidative stress and inflammatory mediators in vitro. Finally, the efficacy of the top candidate will be assessed through orotracheal delivery in a rat model of emphysema. The resulting product will be further developed as an inhalable drug in Phase II through bioprocess development, formulation, toxicology studies and pharmacokinetic studies. Success in this endeavor will yield a clinical drug that limits the progression of emphysema and increases the duration and quality of life for patients. It would likely also be useful for other chronic pulmonary diseases including cystic fibrosis and alpha- 1 antitrypsin deficiency.