Mutant Polypeptides of Fibroblast Growth Factor 1
Human fibroblast growth factor-1 (FGF-1) is a potent human mitogen for a variety of cell types including vascular endothelial cells, and can stimulate such cells to develop neovasculature capable of relieving ischemia. For this reason, FGF-1 is an angiogenic factor with potential applicability in "angiogenic therapy”.
The present inventions describe several mutant polypeptides of the Î²-trefoil protein human fibroblast growth factor-1 (FGF-1) which greatly exceed the wild-type polypeptide in ability to stimulate human fibroblasts to proliferate. The amino acid sequence of the FGF-1 mutants, as well as the methods of treating fibroblasts and of stimulating mitogenesis of the fibroblast leading to tissue healing are described. The purified polypeptides of the present invention exhibit from approximately fifteen to one thousand times more mitogenic activity than wild-type FGF-1 in stimulating fibroblasts to proliferate.
These mutants of human FGF-1 with enhanced stability and mitogenic potency can be used as second generation forms of FGF-1 in angiogenic therapy. Enhanced stability may preclude the need for added heparin in the formulation of FGF-1 for therapeutic use. Additionally, the enhanced thermal stability may translate to longer shelf-life and minimization of aggregation during storage. The enhanced mitogenicity (possibly related to enhanced stability) may provide for smaller dosages for equivalent efficacy.