MUTATED FIBROBLAST GROWTH FACTOR (FGF) 1 AND METHODS OF USE

摘要

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

主权项

1. A method of reducing blood glucose in a mammal, comprising:
(a) administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 1 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF1 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, wherein the mutated mature FGF1 protein comprises:
a deletion of at least six contiguous N-terminal amino acids;at least one point mutation;or combinations thereof; (b) administering a therapeutically effective amount of a fibroblast growth factor receptor (FGFR) 1c-binding protein to the mammal, or a nucleic acid molecule encoding the FGFR1c-binding protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose, wherein the FGFR1c-binding protein comprises a multimer of FGFR1c-binding proteins; or (c) combinations of (a) and (b).