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Notch inhibition in the treatment and prevention of obesity

a notch and obesity technology, applied in the direction of antibody medical ingredients, peptide/protein ingredients, metabolic disorders, etc., can solve the problems of increased risk and activeness, and achieve the effects of preventing proteolytic cleavage, increasing risk, and increasing notch expression levels

Inactive Publication Date: 2016-05-12
THE BRIGHAM & WOMEN S HOSPITAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to methods of treating or preventing obesity and metabolic diseases by administering a therapeutically effective amount of a compound that inhibits or modulates the NOTCH signaling pathway. The invention proposes the use of a variety of methods to inhibit or modify the activity of the NOTCH pathway, including but not limited to inhibition of gamma-secretase and suppression of NOTCH receptor cleavage, inhibition of NOTCH trafficking to the cell membrane, suppression of expression or function of ligands or receptors, inhibition of ligand turnover, cleavage, and endocytosis, modification of NOTCH glycosylation, alteration of ubiquitination of NOTCH components, blocking antibodies against NOTCH components, small molecules and peptides that interfere with expression, function, or activity of NOTCH components, and gamma-secretase inhibitors. The invention also proposes the use of expression or activity of Notch components as imaging biomarkers to identify patients with metabolic disorders and predict future development of metabolic syndrome and its complications.

Problems solved by technology

Results indicating that higher levels of NOTCH activity are present in the patient may be an indication of increased risk.

Method used

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  • Notch inhibition in the treatment and prevention of obesity
  • Notch inhibition in the treatment and prevention of obesity
  • Notch inhibition in the treatment and prevention of obesity

Examples

Experimental program
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Effect test

example 1

Delta-Like 4 Participates in the Pathogenesis of Atherosclerosis and Obesity: A Potential Common Mechanism for Cardiometabolic Disorders

[0085]The present example examines whether the Notch ligand Delta-like 4 (Dll4) contributes to the pathogenesis of cardiometabolic disorders.

[0086]A. Methods

[0087]Mice and anti-Dll4 Ab Treatment

[0088]Eight-week-old male Ldlr− / − mice were purchased from The Jackson Laboratory. Ldlr− / − mice were fed a high-fat, high-cholesterol diet (D12108, Research Diets; 40% fat, 1.25% cholesterol) from 8 weeks of age through the completion of the study. All mice were housed on a 12-hour light / dark cycle, with food and water ad libitum. Animal care and experimentation was approved by the Harvard Medical School Institutional Animal Care and Use Committee. Ldlr− / − mice were assigned randomly to two groups and were injected with 250 μg of hamster anti-mouse Dll4 antibody (Dll4 Ab) or isotype control IgG (IgG) (BioXcell) intraperitoneally twice a week from 8 weeks of a...

example 2

Notch3 Signaling in Macrophages Promotes Obesity, Atherosclerosis and Arterial Calcification in Hypercholesterolemic Mice

[0139]To test the hypothesis that Notch signaling in macrophages promotes cardiometabolic disorders, including obesity, metabolic syndrome, atherosclerosis and vascular calcification, macrophage-selective Notch3-ICD transgenic (Notch3tg) mice under control of the macrophage SR-A promoter / enhancer were used. The findings from the study suggest that Notch3 signaling induces a proinflammatory macrophage phenotype and that Notch3 activation in macrophages promotes atherosclerosis, arterial calcification, and visceral fat obesity in vivo.

[0140]A. Methods

[0141]Animal Preparation

[0142]All experiments conform to a protocol approved by the Standing Committee on Animals of Harvard Medical School. Two independent macrophage-selective Notch3 intracellular domain transgenic (Notch3tg) mice were established under the control of the macrophage scavenger receptor A (SR-A) promote...

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PUM

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Abstract

The present invention is directed to methods of treating or preventing obesity by administering agents that inhibit the NOTCH signaling pathway. Antibodies that inhibit the binding of Delta like 4 ligand (Dll4) to NOTCH receptors may be used for this purpose.

Description

RELATED APPLICATIONS AND INCORPORATION BY REFERENCE[0001]This application is a division of U.S. Ser. No. 13 / 461,365, filed on May 1, 2012. U.S. Ser. No. 13 / 461,365 is a continuation-in-part application of international patent application Serial No. PCT / US2010 / 054798 filed 29 Oct. 2010, which published as PCT Publication No. WO 2011 / 053822 on 5 May 2011, and which claims benefit of U.S. provisional patent application 61 / 257,026, filed on 1 Nov. 2009.[0002]Reference is made to U.S. Pat. No. 8,133,857 and U.S. patent application Ser. No. 13 / 358,425, filed on Jan. 25, 2012 (now abandoned).[0003]The foregoing applications, and all documents cited therein or during their prosecution (“appin cited documents”) and all documents cited or referenced in the appin cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specificat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/22
CPCC07K16/22C07K2317/76C07K2317/20A61K2039/505A61K38/1709A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/00A61P9/02A61P9/08A61P9/10A61P13/12A61P15/10A61P27/02C12N15/113C12N15/1138C12N2310/14A61K39/3955
Inventor AIKAWA, MASANORIFUKUDA, DAIJUMIYAZAKI, TETSUROAIKAWA, ELENA
Owner THE BRIGHAM & WOMEN S HOSPITAL INC
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