Compoitions and methods for modulating thermogenesis using pth-related and egf-related compounds

Patent metadata

Field	Value
Publication number	US-2016175401-A1
Application number	US-201414909163-A
Country	US
Kind code	A1
Filing date	Jul 30, 2014
Priority date	Jul 31, 2013
Publication date	Jun 23, 2016
Grant date	—

Abstract

The present invention provides compositions and methods for modulating thermogenesis and related activities by modulating PTH-related and EGF-related expression and activity. Also provided are methods for preventing or treating metabolic disorders in a subject through modulation of PTH-related and EGF-related expression and activity.

First claim

What is claimed:

1 . A method of modulating a metabolic response comprising contacting a cell with an agent that modulates the expression and/or activity of one or more biomarkers listed in Table 1, or orthologs and fragments thereof, to thereby modulate the metabolic response.

2 . The method of claim 1 , wherein the one or more biomarkers is selected from the group consisting of PTHrP, PTH, BTC, EREG, HBEGF, AREG, EGF, EPGN, and TGFA, and orthologs and fragments thereof.

3 . The method of claim 2 , wherein the one or more biomarkers is selected from the group consisting of PTHrP, PTH, BTC, EREG, and HBEGF, and orthologs and fragments thereof.

4 . The method of claim 3 , wherein the one or more biomarkers is selected from the group consisting of human PTHrP, human PTH, a human PTHrP fragment comprising or consisting of amino acid residues 1-34, a human PTH fragment comprising or consisting of amino acid residues 1-34, and orthologs thereof.

5 . The method of claim 1 , wherein the one or more biomarkers is selected from the group consisting of SEQ ID NOs:1-44 and nucleic acids and polypeptides having a sequence at least 80% identical to one or more of SEQ ID NOs:1-44, and fragments thereof.

6 . The method of claim 1 , wherein expression and/or activity of the one or more biomarkers is upregulated.

7 . The method of claim 6 , wherein expression and/or activity of the one or more biomarkers is upregulated using an agent selected from the group consisting of a nucleic acid molecule encoding the one or more biomarkers or fragment thereof, a polypeptide of the one or more biomarkers or fragment(s) thereof, and a small molecule that binds to the one or more biomarkers.

8 . The method of claim 7 , wherein the polypeptide is selected from the group consisting of human PTHrP, human PTH, a human PTHrP fragment comprising or consisting of amino acid residues 1-34, a human PTH fragment comprising or consisting of amino acid residues 1-34, and fusion proteins and orthologs thereof.

9 . The method of claim 8 , wherein the polypeptide lacks a signal peptide.

10 . The method of claim 8 , wherein the polypeptide further comprises a heterologous polypeptide.

11 . The method of claim 10 , wherein the heterologous polypeptide is selected from the group consisting of a signal peptide, a peptide tag, a dimerization domain, an oligomerization domain, an agent that promotes plasma solubility, an agent that increases in vivo protein half-life, an antibody or fragment thereof, and an Fe domain.

12 . The method of any one of claims 7 - 11 , further comprising contacting the cell with an additional agent that increases the metabolic response.

13 . The method of claim 1 , wherein expression and/or activity of the one or more biomarkers is downregulated.

14 . The method of claim 13 , wherein expression and/or activity of the one or more biomarkers is downregulated using an agent selected from the group consisting of an antisense nucleic acid molecule, an RNA interference molecule, a blocking antibody that binds to the polypeptide of the one or more biomarkers and/or the receptor of such polypeptides, a non-activating form of the polypeptide of the one or more biomarkers or fragments thereof and/or the receptor of such polypeptides, and a small molecule that binds to the one or more biomarkers.

15 . The method of claim 14 , wherein the antisense, RNA interference, blocking antibodies, non-activating polypeptides, and small molecules bind to one or more biomarkers selected from the group consisting of human PTHrP, human PTH, a human PTHrP fragment comprising or consisting of amino acid residues 1-34, a human PTH fragment comprising or consisting of amino acid residues 1-34, and orthologs thereof.

16 . The method of claim 14 , wherein the blocking antibodies and small molecules bind to the PTH1R, EGFR, or ERBB4 receptors.

17 . The method of any one of claims 10 - 15 , further comprising contacting the cell with an additional agent that decreases the metabolic response.

18 . The method of claim 1 , wherein the step of contacting occurs in vivo.

19 . The method of claim 1 , wherein the step of contacting occurs in vitro.

20 . The method of claim 1 , wherein the cell is selected from the group consisting of fibroblasts, myoblasts, myocytes, adipoblasts, adipocytes, hepatocytes, and neural cells.

21 . The method of claim 1 , wherein the metabolic response is selected from the group consisting of:
a) modified expression of one or more markers selected from the group consisting of: cidea, adiponectin, adipsin, otopetrin, type II deiodinase, cig30, ppar gamma 2, pgc1α, ucp1, clov13, cAMP, Prdm16, cytochrome C, cox4i1, coxIII, cox5b, cox7a1, cox8b, glut4, atpase b2, cox II, atp5o, ndufb5, ap2, ndufs1, GRP109A, acylCoA-thioesterase 4, EARA1, claudin1, PEPCK, fgf21, acylCoA-thioesterase 3, and dio2; b) modified thermogenesis in adipose cells; c) modified differentiation of adipose cells; d) modified insulin sensitivity of adipose cells and/or blood glucose levels; e) modified basal respiration, uncoupled respiration, and/or total respiration; f) modified hepatosteatosis; g) modified obesity or appetite; h) modified insulin secretion of pancreatic beta cells; i) modified cardiac function; j) modified cardiac hypertrophy; and k) modified muscle hypoplasia.

22 . A method of assessing the efficacy of an agent that modulates the expression and/or activity of one or more biomarkers listed in Table 1, or orthologs and fragments thereof, for modulating a metabolic response in a subject, comprising:
a) detecting in a subject sample at a first point in time, the expression and/or activity of the expression and/or activity of the one or more biomarkers; b) repeating step a) during at least one subsequent point in time after administration of the agent; and c) comparing the expression and/or activity detected in steps a) and b), wherein a significantly lower biomarker expression and/or activity in the first subject sample relative to at least one subsequent subject sample, indicates that the agent increases the metabolic response in the subject and/or wherein a significantly higher biomarker expression and/or activity in the first subject sample relative to at least one subsequent subject sample, indicates that the test agent decreases the metabolic response in the subject.

23 . The method of claim 22 , wherein the one or more biomarkers is selected from the group consisting of PTHrP, PTH, BTC, EREG, HBEGF, AREG, EGF, EPGN, and TGFA, and orthologs and fragments thereof.

24 . The method of claim 23 , wherein the one or more biomarkers is selected from the group consisting of PTHrP, PTH, BTC, EREG, and HBEGF, and orthologs and fragments thereof.

25 . The method of claim 24 , wherein the one or more biomarkers is selected from the group consisting of human PTHrP, human PTH, a human PTHrP fragment comprising or consisting of amino acid residues 1-34, a human PTH fragment comprising or consisting of amino acid residues 1-34, and orthologs thereof.

26 . The method of claim 22 , wherein the one or more biomarkers is selected from the group consisting of SEQ ID NOs: 1-44 and nucleic acids and polypeptides having a sequence at least 80% identical to one or more of SEQ ID NOs: 1-44, and fragments thereof.

27 . The method of claim 22 , wherein the agent is selected from the group

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Spiegelman Bruce M
• Kir Serkan

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K14/635

  Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides · CPC title

• G01N33/74

  involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors} · CPC title