Fgf2 truncations and mutants and uses thereof
AssigneeThe Salk Institute for Biological Studies
InventorsRonald M. Evans, Michael Downes, Annette Atkins, Jae Myoung Suh, Ruth T. Yu
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Abstract
The present disclosure provides FGF2 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Thus, the disclosed mutant FGF2 proteins can be used to treat one or more metabolic diseases. In some examples, mutant FGF2 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, for example to treat a metabolic disorder are also provided.
Claims20
A method of reducing blood glucose in a mammal, comprising:
- administering a therapeutically effective amount of a mutated mature fibroblast growth factor (FGF) 2 protein to the mammal, or a nucleic acid molecule encoding the mutated mature FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing the blood glucose,
- wherein the mutated mature FGF2 protein comprises:
- at least one point mutation, wherein the at least one point mutation comprises a mutation at one or more of G19, H25, F26, K30, Y33, R53, Q65, C96, E105, N111, Y112, N113, T121, K128, R129, Q132, K134, and S137, wherein the numbering refers to the sequence shown SEQ ID NO:
- 3;
- and
- optionally a deletion of at least six contiguous N-terminal amino acids.
A method of reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis, or combinations thereof, in a mammal, comprising:
- administering a therapeutically effective amount of a mutated mature FGF2 protein to the mammal, or a nucleic acid molecule encoding the mutated FGF2 protein or a vector comprising the nucleic acid molecule, thereby reducing fed and fasting blood glucose, improving insulin sensitivity and glucose tolerance, reducing systemic chronic inflammation, ameliorating hepatic steatosis in a mammal, or combinations thereof, in a mammal,
- wherein the mutated mature FGF2 protein comprises:
- at least one point mutation, wherein the at least one point mutation comprises a mutation at one or more of G19, H25, F26, K30, Y33, R53, Q65, C96, E105, N111, Y112, N113, T121, K128, R129, Q132, K134, and S137, wherein the numbering refers to the sequence shown SEQ ID NO:
- 3;
- and
- optionally a deletion of at least six contiguous N-terminal amino acids.
An isolated mutated mature fibroblast growth factor (FGF) 2 protein
- comprising at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:
- 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44,
- comprising SEQ ID NO:
- 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44, or
- consisting of SEQ ID NO:
- 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44, and
- wherein the mutated mature FGF2 protein is not SEQ ID NO:
- 2, 3 or 5.
Dependencies are inferred from the claim text.