SBIR Phase II: Development of Bioengineered Anticoagulant Heparin from a Non-Animal Source

这一小型企业创新研究(SBIR)第二阶段项目的更广泛影响是消除医学界对动物来源肝素的依赖。肝素是目前从猪肠中生产的一种重要的抗凝药物，主要来源是中国。在美国，每天有超过30万剂肝素被注射，全球肝素市场价值650万美元。在过去的12年里，猪瘟减少了猪的数量，限制了肝素的可用数量，导致了出于经济动机的掺假和肝素配给。使用从猪肠中提取的肝素在一些患者中也会导致肝素引起的血小板减少，这种情况可以通过生物工程肝素来减少。该项目推进了从基因工程细胞中生产肝素的技术，从而消除了从动物那里获取药物的需要，确保了其国内生产。拟议中的项目旨在增加从细胞系中生产生物工程肝素。以前的工作已经产生了产生抗凝血剂效力相当于药物肝素的材料的细胞系。目前的挑战是提高产量，以具有竞争力的价格满足患者的需求。将对细胞进行基因工程，通过过度表达负责肝素生产的酶来提高它们的生产能力。此外，用于培养细胞的细胞培养液和饲料已经针对蛋白质生产进行了优化，将重新配制配方，以优化哺乳动物细胞中肝素的生产。其目标是将细胞的生产率提高约100倍，这将使生物工程肝素的规模变得负担得起，为从哺乳动物细胞生产多糖类药物的开发铺平道路。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact of this Small Business Innovation Research (SBIR) Phase II project is to eliminate the medical community’s dependence on heparin derived from animal sources. Heparin is an essential anticoagulant drug currently produced from pig intestines, primarily sourced in China. Over 300,000 doses of heparin are administered daily in the US and the global heparin market is valued at $6.5 B. Over the past 12 years, swine diseases that reduced the pig population and limited the amount of heparin available led to economically motivated adulteration and rationing of heparin. Use of heparin derived from pig intestines also results in heparin-induced thrombocytopenia in some patients, which can be reduced via bioengineered heparin. This project advances technology to produce heparin from genetically engineered cells to eliminate the need to source the drug from animals, securing its domestic production. The proposed project pursues increasing the production of bioengineered heparin from cell lines. Previous work has resulted in cell lines that produce material with anticoagulant potency that equals pharmaceutical heparin. The current challenge is to increase yield to meet patient needs at a competitive price. Cells will be genetically engineered to increase their production capacity by overexpressing the enzymes responsible for heparin production. Additionally, the cell culture medium and feeds used to grow the cells, which have been optimized for protein production, will be reformulated to optimize production of heparin in mammalian cells. The objective is to increase the productivity of cells about 100-fold, which will make bioengineered heparin affordable at scale, paving the way for the development of polysaccharide drugs produced from mammalian cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.