STTR Phase I: Novel bioreactors for production of metabolically engineered heparin in Chinese hamster ovary cells

这项小型企业技术转移（STTR）一期项目提议将一种新型代谢工程中国仓鼠卵巢（CHO）细胞系与一种独特、高性能、连续细胞培养生物反应器相结合，以证明从CHO细胞中生产生物工程肝素的商业可行性。这种CHO细胞系过度表达肝素生物合成途径中的关键酶，导致与肝素药理等效的产物水平增加。这些细胞将在该公司专有的吸液基质生物反应器中生长，该反应器可能实现高密度，在小占地面积内连续生产培养物，从而将产品的制造成本降低数倍。目的是证明该工程CHO细胞系可以在该生物反应器中长时间生长，同时保持高生产率和产品质量。这有望通过优化各种物理和化学参数，开发独特的监测系统，以及持续评估与肝素生产相关的代谢，生产力和质量属性来实现。如果这项研究成功，其更广泛的商业影响将是推动新型生物反应器系统的开发，可能会使制造治疗药物的制造成本降低数倍，并开发生物工程肝素，这是一种广泛使用的治疗药物的更安全的版本。肝素是现代医学中应用最广泛的抗凝血药物（约70亿美元），每年生产100吨肝素。然而，目前的生产方法依赖于从已知和有记录的致命污染和疾病发生率的动物组织中提纯。实现这些目标将促进以更具成本效益的方式引进新型药品，从而对人类健康产生重大影响。

This Small Business Technology Transfer (STTR) Phase I project proposes to combine a novel metabolically engineered Chinese hamster ovary (CHO) cell line with a unique, high performance, continuous cell-culture bioreactor to demonstrate the commercial viability of producing a bioengineered heparin from CHO cells. This CHO cell line overexpresses critical enzymes in the heparin biosynthesis pathway, resulting in increased levels of a product that is the pharmacological equivalent to heparin. These cells will be grown in the company's proprietary wicking matrix bioreactor that can potentially enable high density, continuously producing cultures in a small footprint, and thus have a multifold reduction in manufacturing cost of goods. The goal is to demonstrate that this engineered CHO cell line can be grown for an extended duration in this bioreactor while maintaining high productivity and product quality. This is expected to be accomplished by optimizing various physical and chemical parameters, developing a unique monitoring system, and continuously assessing metabolic, productivity, and quality attributes associated with heparin production.The broader/commercial impacts of the proposed research, if successful, will be to advance the development of a novel bioreactor system, potentially with a multifold reduction in manufacturing cost of making therapeutics, and the development of a bioengineered heparin, a substantially safer version of a widely used therapeutic. Heparin is the most widely used anticoagulant drug in modern medicine (~$7B) with 100 tons of heparin being produced annually. However, current production methods rely on purification from animal tissues with known and documented deadly incidences of contamination and disease. Achievement of these objectives will have a substantial impact on human health by facilitating the introduction of novel pharmaceuticals in a more cost-effective manner.