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

开发非抗凝重组肝素治疗慢性阻塞性肺病致病三联征

基本信息

批准号：
10382108
负责人：
Charles Alexander Glass
金额：
$ 32.19万
依托单位：
TEGA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-05 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382108
关键词：
Adrenal Cortex Hormones Alveolar Animal Model Anti-Inflammatory Agents Anticoagulants Anticoagulation Antioxidants Binding Biochemical Biological Assay Blood Breathing California Cause of Death Cell Line Cells Cessation of life Charge Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Clinic Clinical Collaborations Consult Cystic Fibrosis Development Disease Disease Progression Dose Drug Kinetics Dust Elastases Electrostatics Endothelial Growth Factors Receptor Exposure to Feasibility Studies Formulation Genetic Engineering Goals Healthcare Heparin Heparitin Sulfate Heparitin sulfotransferase Human In Vitro Inflammation Inflammation Mediators Inhalation Inhalation Exposure Inhalation Therapy Injections Life Lung Mammalian Cell Mast Cell Neoplasm Modeling Occupational Oxidative Stress Pathogenicity Patients Peptide Hydrolases Pharmaceutical Preparations Phase Population Prevalence Production Property Proteins Pulmonary Emphysema Quality of life Rattus Recombinants SU 5416 Series Sputum Sulfate Technology Testing Therapeutic Therapeutic Intervention Therapeutic Uses Toxicology Treatment Efficacy Triad Acrylic Resin Universities VEGFA gene Virginia Work alpha 1-Antitrypsin Deficiency antagonist base bioprocess cellular engineering cigarette smoke cigarette smoking cytokine drug development effective therapy elastase inhibitor functional disability improved in vivo in vivo evaluation inhibitor interest novel novel strategies overexpression palliative prevent smoking exposure success targeted treatment

项目摘要

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.

项目概要该提案描述了一种治疗 COPD（慢性阻塞性肺疾病）肺气肿的新策略使用由基因工程哺乳动物细胞生产的独特定制的硫酸乙酰肝素来治疗疾病）。肺气肿是慢性阻塞性肺病 (COPD) 的主要组成部分，这种疾病困扰着高达 5% 的人口，是第四大疾病目前尚无药物被证明能有效治愈或延迟死亡。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。针对疾病进展的三个主要驱动因素（蛋白酶、氧化应激和炎症），并且可以吸入进行局部治疗，肝素的用途受到其抗凝剂的限制。 TEGA Therapeutics 的重组硫酸乙酰肝素生产技术能够实现靶向消除。 3-O-硫酸酯基团对于抗凝血活性至关重要，同时保持抗弹力松解、抗- 产生不含 3-O- 的硫酸乙酰肝素的哺乳动物细胞系。硫酸盐将被基因改造以改善对肺气肿驱动因素的抑制作用。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。最佳候选药物的疗效将通过大鼠肺气肿模型中的经口气管输送进行评估。由此产生的产品将通过生物工艺进一步开发为二期吸入药物开发、配方、毒理学研究和药代动力学研究将取得成功。一种临床药物，可限制肺气肿的进展并延长患者的生活时间和质量它也可能对其他慢性肺部疾病有用，包括囊性纤维化和α-肺部疾病。 1.抗胰蛋白酶缺乏。