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.

项目摘要该提案描述了治疗COPD中肺气肿的新型策略（慢性阻塞性肺疾病）使用由基因设计的哺乳动物细胞产生的独特量身定制的硫酸乙酰肝素。肺气肿是COPD的主要组成部分，COPD疾病遭受高达5％的人口的疾病，是第四个疾病美国的主要死因。目前尚无证明有效治愈或延迟的药物疾病的进展。靶向疗法几乎没有临床益处，但肝素具有多点对疾病进展的三个主要驱动因素（蛋白酶，氧化应激和炎症），可以纳入局部治疗。肝素的实用性受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紧急 3-O硫酸盐基团对于抗凝活性至关重氧化和抗炎特性。哺乳动物细胞系，产生硫酸乙酰肝素无3-O- 硫酸盐将经常设计以改善肺气肿驱动因素的抑制作用。然后这些产品将是经过测试以评估其抑制蛋白酶，氧化应激和炎症介质的能力。最后，顶级候选人的效率将通过气管递送在大鼠肺气肿模型中进行评估。生成的产品将作为II阶段通过生物处理中进一步开发为可吸入药物开发，公式，毒理学研究和药代动力学研究。这项努力的成功将产生一种限制肺气肿进展并增加生活持续时间和生活质量的临床药物患者。它也可能对其他慢性肺部疾病（包括囊性纤维化和α-）有用。 1抗胰蛋白酶缺乏症。