Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.68542
Keywords
diamine oxidase; histamine; heparin; heparan sulfate proteoglycan; clearance; half-life; Mouse; Rat; Other
Categories
Funding
- Austrian Science Fund [T1135]
- Sigrid Juseliuksen Saatio
- Medicinska Understodsforeningen Liv och Halsa
- Austrian Science Fund (FWF) [T1135] Funding Source: Austrian Science Fund (FWF)
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By mutating the heparin-binding motif of hDAO, the plasma clearance rate was successfully reduced in rodents, showing potential for treating diseases characterized by high plasma histamine concentrations.
Background: Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations. Methods: Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined. Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short alpha-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents. Conclusions: The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues. Funding: Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understodsforening Liv och Halsa rft (TAS and SeV).
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