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

SBIR 第二阶段：开发非动物来源的生物工程抗凝肝素

• 批准号: 2026188
• 负责人: Charles Glass
• 金额: $ 99.99万
• 依托单位: TEGA Therapeutics Inc
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2026188&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Development; Bioengineered

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.

这项小型企业创新研究（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。肝素是一种基本的抗凝药物，目前主要从中国的猪肠中生产。在美国，每天施用超过300，000剂肝素，全球肝素市场价值65亿B美元。在过去的12年里，猪的疾病减少了猪的数量，限制了肝素的可用量，导致了经济动机的肝素掺假和配给。使用猪肠来源的肝素也会导致一些患者出现肝素诱导的血小板减少症，这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，消除了从动物中获取药物的需要，确保了国内生产。拟议的项目旨在增加从细胞系生产生物工程肝素。以前的工作已经导致细胞系产生的材料具有抗凝效力，相当于药用肝素。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。细胞将被基因工程改造，通过过度表达负责肝素生产的酶来提高其生产能力。此外，将重新配制用于培养细胞的细胞培养基和饲料（已针对蛋白质生产进行了优化），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力提高约100倍，这将使生物工程肝素在规模上负担得起，为开发从哺乳动物细胞生产的多糖药物铺平道路。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Advancing to Recombinant Heparin

推进重组肝素

• 发表时间: 2021
• 期刊: American pharmaceutical review
• 作者: Thacker, Bryan;Glass, Charles;Sharfstein, Susan
• 通讯作者: Sharfstein, Susan

Multiplex genome editing of mammalian cells for producing recombinant heparin

用于生产重组肝素的哺乳动物细胞多重基因组编辑

• DOI: 10.1016/j.ymben.2022.01.002
• 发表时间: 2022
• 期刊: Metabolic engineering
• 影响因子: 8.4
• 作者: Thacker, B;Thorne, K;Cartwright, C;Park, J;Glass, K;Chea, A;Kellerman, B;Lewis, N;Wang, Z;Di Nardo, A
• 通讯作者: Di Nardo, A

Recombinant Heparin: An Old Drug for the Modern World

重组肝素：现代世界的老药

• 发表时间: 2021
• 期刊: Research and practice in thrombosis and haemostasis
• 影响因子: 4.6
• 作者: Thacker, Bryan;Thorne, Kristen;Cartwright, Colin;Park, Jeeyoung;Glass, Kimberly;Chea, Annie;Jeske, Walter;Walenga, Jeanine;Sharfstein, Susan;Esko, Jeffrey
• 通讯作者: Esko, Jeffrey