SBIR Phase I: Bioengineered Recombinant Anticoagulant Heparin

SBIR 第一期：生物工程重组抗凝肝素

• 批准号: 1842736
• 负责人: Charles Glass
• 金额: $ 22.5万
• 依托单位: TEGA Therapeutics Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1842736&HistoricalAwards=false
• 关键词: SBIR; Phase; Bioengineered; Recombinant; Anticoagulant

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project will be to develop an alternative source of pharmaceutical heparin using engineered cultured mammalian cells. Heparin is a widely prescribed anticoagulant (blood thinner), critical for surgical operations and for patients that otherwise have risks of blood clotting. Over 300,000 doses are administered per year in the US alone. Currently, heparin is prepared from animal tissues, primarily pig intestines in China, which has regulatory agencies in the US and other countries concerned. For one reason, heparin manufacturing is difficult to regulate in China as evidenced by the heparin adulteration crisis in 2008 that led to allergic reactions and over 250 deaths worldwide. In addition, there is concern that the Chinese pig population will not be able to keep up with the increasing demand. The FDA is considering reintroducing heparin produced from beef cattle as an alternative source, however, bovine heparin is still subject to complications involving animal tissues and it has different anticoagulant properties, which complicates dosing. The current proposal develops cell-based production in which the entire supply chain can be under GMP control and scalable as needed with no dependence on the number and health of an animal population.The intellectual merit of this SBIR Phase I project is to genetically engineer cells to produce a heparin product that can be manufactured for pharmaceutical use. Cellular production can be entirely under GMP control, and cell engineering provides opportunities to produce heparin with improved properties. A survey of clinicians that use heparin overwhelmingly identified heparin induced thrombocytopenia (HIT) as a serious detrimental side effect. HIT can lead to blood clots, stroke, heart attack and loss of life and limb. Treatment is complicated and expensive. HIT is an allergic reaction caused when heparin binds to a specific protein in the blood called platelet factor 4 (PF4). PF4 binding depends on elements of heparin structure that are not involved in heparin's anticoagulant activities. Through cell engineering, heparin molecules with an altered structure will be produced that have reduced affinities for PF4, while maintaining potent anticoagulant properties. In addition, heparin has demonstrated efficacy in other areas such as inflammation and cancer that are not involved in blood clotting. Through cell engineering, heparin structures also could be tailored for these additional applications.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.

该小型企业创新研究（SBIR）I期项目的更广泛影响/商业潜力将是使用工程化培养的哺乳动物细胞开发药用肝素的替代来源。肝素是一种广泛使用的抗凝剂（血液稀释剂），对于外科手术和其他有凝血风险的患者至关重要。仅在美国，每年就有超过30万剂疫苗被注射。目前，肝素是从动物组织中制备的，在中国主要是猪肠，在美国和其他相关国家有监管机构。其中一个原因是，肝素生产在中国很难监管，2008年肝素掺假危机导致过敏反应和全球250多人死亡就是明证。此外，人们担心中国生猪数量将无法跟上不断增长的需求。FDA正在考虑重新引入由肉牛生产的肝素作为替代来源，然而，牛肝素仍然受到涉及动物组织的并发症的影响，并且它具有不同的抗凝特性，这使得给药复杂化。目前的提案开发了基于细胞的生产，其中整个供应链可以在GMP控制下，并根据需要进行扩展，而不依赖于动物种群的数量和健康状况。SBIR第一阶段项目的智力价值是基因工程细胞，以生产可用于制药用途的肝素产品。细胞生产可以完全在GMP控制下，细胞工程提供了生产具有改进性质的肝素的机会。一项对使用肝素的临床医生的调查压倒性地确定肝素诱导的血小板减少症（HIT）是一种严重的有害副作用。HIT可导致血栓、中风、心脏病发作以及生命和肢体的丧失。治疗复杂且昂贵。HIT是一种过敏反应，当肝素与血液中称为血小板因子4（PF 4）的特定蛋白质结合时引起。PF 4结合依赖于肝素结构的元素，这些元素不参与肝素的抗凝活性。通过细胞工程，将产生具有改变的结构的肝素分子，其对PF 4的亲和力降低，同时保持有效的抗凝特性。此外，肝素已在其他领域显示出疗效，如炎症和癌症，不涉及血液凝固。通过细胞工程，肝素结构也可以为这些额外的应用定制。这个奖项反映了NSF的法定使命，并已被认为是值得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的支持。