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Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

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Science Translational Medicine  06 Sep 2017:
Vol. 9, Issue 406, eaan5954
DOI: 10.1126/scitranslmed.aan5954

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A reliable animal-free heparin drug

Full-sized and low–molecular weight heparins are widely used to treat a variety of clotting disorders. Although low–molecular weight heparins are safer and more convenient to use than full-size heparin, they are still animal-derived products that present a risk of contamination and supply chain interruptions and are limited with respect to standardization and reversibility of anticoagulation. A method developed by Xu et al. offers a potential alternative to animal-sourced heparins in the form of a chemical synthesis process that can be scaled up to produce heparin dodecasaccharides with reversible activity in adequate quantities for potential therapeutic use.

Abstract

Low–molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.

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