A human recombinant haemoglobin designed for use as a blood substitute

• Published in: Nature (London) 1992-03, Vol.356 (6366), p.258-260
• Main Authors: Looker, Douglas, Abbott-Brown, Debbie, Cozart, Paul, Durfee, Steven, Hoffman, Stephen, Mathews, Antony J, Miller-Roehrkh, Jeanne, Shoemaker, Steven, Trimble, Stephen, Fermi, Giuilio, Komiyama, Noboru H, Nagai, Kiyoshi, Stetler, Gary L
• Format: Article
• Language: English
• Subjects: affinity; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; beta -globin; Biochemistry; Biological and medical sciences; Biotechnology; Blood; Blood Substitutes - adverse effects; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Crystallization; E coli; Escherichia coli - genetics; expression; genes; Globins - genetics; Globins - metabolism; haemoglobin; Half-Life; Hemoglobins - biosynthesis; Hemoglobins - genetics; Hemoglobins - metabolism; Humanities and Social Sciences; Humans; Kidney Diseases - chemically induced; letter; Macromolecular Substances; man; Medical sciences; Molecular Structure; multidisciplinary; Mutation; Oxygen; Oxygen - metabolism; Pathogens; production; Rats; Rats, Inbred Strains; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - metabolism; recombinants; Science; Science (multidisciplinary); Transfusions. Complications. Transfusion reactions. Cell and gene therapy; vectors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/356258a0

THE need to develop a blood substitute is now urgent because of the increasing concern over blood-transmitted viral and bacterial pathogens 1 . Cell-free haemoglobin solutions 2,3 and human haemoglobin synthesized in Escherichia coli 4 and Saccharomyces cerevisiae 5 have been investigated as potential oxygen-carrying substitutes for red blood cells. But these haemoglobins cannot be used as a blood substitute because (1) the oxygen affinity in the absence of 2,3-bisphosphoglycerate is too high to allow unloading of enough oxygen in the tissues 6 , and (2) they dissociate into αβ dimers 7 that are cleared rapidly by renal filtration 8–10 , which can result in long-term kidney damage 7–9 . We have produced a human haemoglobin using an expression vector containing one gene encoding a mutant β-globin with decreased oxygen affinity and one duplicated, tandemly fused α-globin gene. Fusion of the two α-globin subunits increases the half-life of this haemoglobin molecule in vivo by preventing its dissociation into αβ dimers and therefore also eliminates renal toxicity.