SBIR Phase I: Bioengineered Recombinant Anticoagulant Heparin

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.