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Mutated fibroblast growth factor (FGF) 1 and methods of use

A technology of fibroblasts and growth factors, applied in the direction of fibroblast growth factors, growth factors/inducers, chemical instruments and methods, etc., can solve problems such as weight gain

Inactive Publication Date: 2016-08-03
SALK INST FOR BIOLOGICAL STUDIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many side effects associated with the use of TZDs, for example, weight gain, liver toxicity, upper respiratory infection, headache, back pain, hyperglycemia, fatigue, sinusitis, diarrhea, hypoglycemia, mild to moderate edema and anemia

Method used

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  • Mutated fibroblast growth factor (FGF) 1 and methods of use
  • Mutated fibroblast growth factor (FGF) 1 and methods of use
  • Mutated fibroblast growth factor (FGF) 1 and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0429] Preparation of mutated FGF1 protein

[0430] Mutant FGF1 proteins can be prepared using known methods (eg, see Xia et al., PLoS One. 7(11):e48210, 2012). Examples are provided below.

[0431]Briefly, a mutant protein encoding FGF1 (e.g., SEQ ID NO: 6, 7, 8, 9, 10, 11, 12, 13, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 173, 174, 175, 177, 178, 179, 181, 182, 183, 185, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, Any of 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 2...

Embodiment 2

[0436] N-terminal truncated FGF1 reduces blood glucose in ob / ob mice

[0437] The inventors have demonstrated that administration of mature rFGF1 to ob / ob mice lowers blood glucose and reduces adverse effects compared to those observed with thiazolidinediones.

[0438] To separate the mitogenic effect of rFGF1 from its hypoglycemic activity, an FGF1 ligand lacking the first 24 residues at the N-terminus (rFGF1 ΔNT (SEQ ID NO: 7)). Based on the crystal structure of the FGF1-FGFR complex, the truncations are predicted to reduce the binding affinity of FGF1 for selected FGFRs, including FGFR4, and thus reduce the mitogenicity of the ligands.

[0439] animal

[0440] Mice were housed in a temperature-controlled environment with a 12-hour light / 12-hour-dark cycle and used according to regulatory protocols consistent with US law. Male ob / ob mice (B6.V-Lep ob J, Jackson Laboratories) and male C57BL / 6J mice received standard or high-fat diet (MI Laboratories Rodent Diet 5001, Harl...

Embodiment 3

[0450] FGF1 mutant protein reduces blood sugar levels in diabetic mice

[0451] The FGF1 mutants shown in Table 3 were tested as described in Example 2.

[0452] As shown in Table 3, up to 12 N-terminal amino acids could be deleted from FGF1 without significantly affecting activity, whereas FGF1 mutants lacking 14 N-terminal amino acids failed to lower glucose in diabetic mice. Mutations that increase the thermostability of FGF1 are generally well tolerated, but glucose-lowering activity is lost in mutants with high stability. Furthermore, mutations in the putative heparan sulfate-binding site had minimal effects on the glucose-lowering effect of FGF1. Notably, the effects of N-terminal deletions and selected stabilizing mutations appeared additive.

[0453]

[0454]

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Abstract

The invention discloses a mutated fibroblast growth factor (FGF) 1 and methods of use. 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 [Beta]-Klotho-binding protein, an FGFRlc-binding protein, a [Beta]-Klotho-binding protein and a FGFRlc-binding protein, a C-terminal region from FGF 19 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.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 61 / 893,766, filed October 21, 2013, U.S. Provisional Application No. 61 / 949,945, filed March 7, 2014, U.S. Provisional Application No. 61 / 949,945, filed April 4, 2014 Priority to Application No. 61 / 975,530, U.S. Provisional Application No. 62 / 019,185, filed June 30, 2014, U.S. Provisional Application No. 62 / 046,038, filed September 4, 2014, all of which Incorporated herein by reference. [0003] Statement of Government Funding [0004] This invention was made with government support under grant numbers DK057978, DK090962, HL088093, HL105278, and ES010337 awarded by the National Institutes of Health, National Human Genome Research Institute. The government has certain rights in this invention. technical field [0005] The present application provides mutated FGF1 proteins, FGFR1c-binding protein multimers, nucleic acids encoding the proteins, and methods of their...

Claims

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Application Information

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IPC IPC(8): A61K38/18A61P3/08A61P3/04C07K14/50C07K19/00
CPCA61K31/421A61K31/422A61K31/4439A61K31/7088A61K38/1825A61K45/06A61P1/16A61P3/04A61P3/06A61P3/08A61P3/10A61P9/12A61P15/00A61P29/00C07K14/501A61K2300/00
Inventor 徐在明M·道恩斯R·M·埃文斯A·阿特金斯R·于
Owner SALK INST FOR BIOLOGICAL STUDIES
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