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

项目总结 这项建议描述了一种治疗慢性阻塞性肺疾病(COPD)中肺气肿的新策略 疾病)使用从基因工程哺乳动物细胞中生产的独特定制的硫酸乙酰肝素。 肺气肿是慢性阻塞性肺疾病的主要组成部分，这种疾病困扰着多达5%的人口，是第四大疾病 在美国居死因首位。目前还没有被证明有效治愈或延缓的药物。 疾病的发展。尽管靶向治疗显示临床益处不大，但肝素有多点作用。 对疾病进展的三个主要驱动因素(蛋白酶、氧化应激和 炎症)，并可吸入进行局部治疗。肝素的用途受到其抗凝剂的限制 活动。Tega Treateutics的重组硫酸乙酰肝素生产技术可以实现有针对性的消除 3-O-硫酸盐基团是抗凝活性所必需的，同时保持抗弹性，抗- 具有氧化和抗炎作用。无3-O-产生硫酸乙酰肝素的哺乳动物细胞系 硫酸盐将经过基因工程改造，以改善对肺气肿驱动因素的抑制。然后，这些产品将被 测试以评估它们在体外抑制蛋白水解酶、氧化应激和炎症介质的能力。最后， 在肺气肿的大鼠模型上，将通过经口气管给药来评估首选候选药物的疗效。 最终产品将在第二阶段通过生物工艺进一步开发为吸入性药物。 开发、配方、毒理学研究和药代动力学研究。这一努力一定会取得成功。 一种临床药物，可限制肺气肿的进展，并提高患者的持续时间和生活质量 病人。它也可能对其他慢性肺部疾病有用，包括囊性纤维化和甲型肝炎。 1抗胰蛋白酶缺乏症。

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.