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US 2026/0199430 A1Published application
Itih5 for use in the treatment of obesity
OwnerEdgar Dahl, Tim Ruhl +2inventors
InventorsEdgar Dahl, Tim Ruhl, Sophia Villwock, Jana Keimes
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Abstract
The invention relates to an isolated or purified ITIH5 polypeptide having the biological activity of a negative regulator of adipogenesis for use in the treatment of obesity in a subject. The invention relates further to methods for identifying ITIH5 epitopes that are effective in reducing weight or weight gain and therefore constitute the basis for identifying synthetic peptides for use in the treatment of obesity. The invention also relates to a method for identifying small molecules that reduce weight or weight gain of a subject by modulation of the ITIH5-adipogenic pathway.
Claims13
1:
- An isolated or purified ITIH5 polypeptide having the biological activity of a negative regulator of adipogenesis for use in the treatment of obesity in a subject, wherein said treatment comprises reducing weight or reducing weight gain, wherein the ITIH5 polypeptide is to be administered to said subject in an amount therapeutically effective to reduce weight or weight gain, and wherein said ITIH5 polypeptide comprises or consists of a peptide selected from the group consisting of:
- a) SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8,
- b) a biologically active fragment, analog, variant, derivative or elongation of a),
- c) a biologically active analog, fragment, variant or derivative of a) having at least 90% identity to SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8,
- d) a polypeptide encoded by the polynucleotide set out in SEQ ID NO:1,
- e) a biologically active fragment, analog, variant, derivative or elongation of d)
- f) a polypeptide encoded by a polynucleotide that hybridizes to the polynucleotide set out in SEQ ID NO:9 under moderately stringent hybridization conditions.
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2:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the biological activity of a negative regulator of adipogenesis is defined by at least one of the following biological effects:
- a. inhibiting the insulin-induced adipogenic differentiation of adipose stem cells (ASCs) into mature adipocytes, and/or
- b. inhibiting proliferation of ASCs.
3:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein said reducing weight or reducing weight gain comprises at least one of the following:
- c. reducing the number of adipose stem/stroma cells, preadipocytes, adipocytes,
- d. reducing differentiation, dysregulated differentiation, and maturation of adipose stem/stroma cells and preadipocytes into mature adipocytes,
- e. reducing the development, enlargement, and fusion of fat vacuoles and supersized lipid droplets,
- f. reducing the amount of adipose tissue,
- g. inhibiting dysfunction of adipose tissue,
- h. reducing the risk for impaired insulin sensitivity and systemic metabolic deterioration in obese state, e.g., type 2 diabetes, non-alcoholic fatty liver disease, dyslipidemia, hypertension, lipotoxicity.
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4:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the subject to be treated is a mammal and preferable a human subject.
5:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the subject to be treated is an obese or overweight subject.
6:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the obesity related attendant symptoms are reduced or prevented, which include inflammation, cardiovascular disease, hypertension, dyslipidemia, heart failure, atherosclerosis, coronary artery disease, stroke, diabetes mellitus type 2, prediabetes, insulin resistance, insulin resistance syndrome (also known as Syndrome X), gall bladder disease, osteoarthritis, sleep apnoea, liver steatosis, obesity-associated liver steatosis, liver inflammation, liver fibrosis, diabetes, obesity-associated fat accretion, obesity-related cancer, infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, hypertension hypercholesterolemia, cholelithiasis, and decreased life expectancy.
7:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the subject does not has diabetes.
8:
- The isolated or purified ITIH5 polypeptide according to claim 1, wherein the route of administration of the ITIH5 polypeptide is intravenous, intraperitoneal, intramuscular, subcutaneous, topical, nasal or pulmonary inhalation.
9:
- A pharmaceutical composition comprising the isolated or purified ITIH5 polypeptide according to claim 1, and at least one pharmaceutically acceptable excipient.
10:
- A method for identifying epitopes of the ITIH5 protein that reduce weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway, comprising:
- a. synthesizing small peptides with a length of 20 to 40 amino acids covering the whole ITIH5 protein or an adipogenesis-active fragment thereof in an overlapping manner;
- b. contacting individual small peptides separately to in vitro cultured adipose stem cells and further incubating the ASCs a preselected time of cell culture under conditions that allow ASC differentiation;
- c. determining the ASC differentiation after a preselected time of cell culture by staining of the cells with a fat-soluble dye that stains neutral triglycerides and lipids;
- d. selection of small peptides inhibiting ASC differentiation as epitopes of ITIH5 that are capable of reducing weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway.
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11:
- A method for identifying epitopes of the ITIH5 protein that reduce weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway, comprising:
- a. synthesizing small peptides with a length of 20 to 40 amino acids covering the whole ITIH5 protein or an adipogenesis-active fragment thereof in an overlapping manner;
- b. contacting individual small peptides separately to in vitro cultured adipose stem cells and further incubating the ASCs a preselected time of cell culture under conditions that allow ASC proliferation;
- c. determining the ASC proliferation by analysing the cells in a cell viability assay such as PrestoBlue® using a detection platform including fluorescence microscopy, flow cytometry, and microplate readers;
- d. selection of peptides inhibiting ASC proliferation as epitopes of ITIH5 that are capable of reducing weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway.
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12:
- A method for identifying synthetic peptides of the ITIH5 protein that reduce weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway, by selecting a bioactive ITIH5 epitope as identified by the method of claim 10.
13:
- A method for identifying mimetic small molecules that reduce weight or reduce weight gain of a subject by modulation of the ITIH5-adipogenic pathway, comprising:
- a. providing a library of small organic compounds;
- b. providing adipocyte precursor cells (APCs) and transfecting them with an expression vector leading to ITIH5 overexpression,
- c. selecting single clones from the cells transfected in step b. showing ITIH5 overexpression,
- d. providing the adipocyte precursor cells (APCs) as chosen in step b. and transfecting with the expression vector of step. b. not containing the ITIH5 expression construct (control vector) leading to control APCs,
- e. selecting single clones from the cells transfected in step d., not exhibiting ITIH5 overexpression (control APCs);
- f. in vitro-cultivating at least one clone of the ITIH5-overexpressing APCs and at least one clone of the control APCs and contacting cells from each clone individually with the same small organic compounds of the library provided in step a.,
- g. analysing the proliferation or the fat cell differentiation of the clones subjected to the small organic compounds of step f., whereas a ITIH mimicking compound leads to a reduction in APC proliferation or fat cell differentiation in the control APC but not in the ITIH5-overexpressing APCs.
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