Screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases

Inactive Publication Date: 2014-01-30
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases. More specifically, it involves testing a collection of substances to see which ones can restore the integrated stress response, which is a way to measure the body's response to stress. The method then selects the substances that have successfully restored the integrated stress response for use in treating inflammatory bowel diseases. The invention also includes a specific agent that can restore the integrated stress response for this purpose.

Problems solved by technology

So far, the ER stress abnormalities as predisposing factor predating histological colitis in UC subjects have not yet been investigated.

Method used

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  • Screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases
  • Screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases
  • Screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases

Examples

Experimental program
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Effect test

example 1

[0132]Unbalanced Endoplasmic Reticulum Stress Reprograms Translation in the Inactive Colon of Patients With Ulcerative Colitis

Material & Methods:

[0133]Patients and Biopsy Specimens.

[0134]All patients included in this study were followed in the Department of Gastroenterology (Beauj on's hospital). The protocol was approved by the local Ethics Committee and written informed consent for this study was obtained from all patients before enrollment. Colonic pinch biopsies were obtained during endoscopic investigations in 11 patients with UC. Surgical colon samples were collected from 15 patients with UC who underwent a colectomy. The diagnosis of UC was based on Lennard-Jones criteria and clinical disease activity was assessed according to the Colitis Activity Index as previously described12. Non-inflamed areas of colonic tissue were punctured endoscopically in each UC patient (5 to 10 biopsies / patients). Surgical samples were processed following the same protocol. Two biopsies were set a...

example 2

[0213]Salubrinal Effect in Vivo

[0214]Ulcerative colitis (UC) is characterized by exclusive colonic involvement with superficial mucosal lesions associated with depletion in goblet cells and decreased secretion of mucins in inflammatory colonic mucosa11. Although it has been proposed that the epithelium of UC patients is diffusely abnormal irrespective to inflammation12, early alterations predating inflammation within colonic epithelial cell remain elusive. It is now evident that impairment of proper ERS resolution by altered unfolded protein response (UPR) in epithelial cells can lead or sensitize to colonic inflammation both in animal2-8 and human studies1,2. However, the consequences of ERS alterations during UC remain misunderstood. The UPR is a carefully orchestrated process involving three proximal sensors PERK, ATF6, and IRE1 that allow cells to cope with a wide variety of stressful conditions. The combined action of these sensors restores cell homeostasis by cessation of prot...

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Abstract

The present invention relates to screening methods and pharmaceutical compositions for the treatment of inflammatory bowel disease. More particularly, the present invention relates to a method for screening a plurality of test substances useful for the prevention or treatment of an inflammatory bowel disease comprising the steps consisting of (a) testing each of the test substances for its ability to restore the integrated stress response and (b) and positively selecting the test substances capable of restoring said integrated stress response. A further aspect of the invention relates to an agent capable of restoring the integrated stress response (ISR) for use in the treatment of an inflammatory bowel disease.

Description

FIELD OF THE INVENTION[0001]The present invention relates to screening methods and pharmaceutical compositions for the treatment of inflammatory bowel diseases.BACKGROUND OF THE INVENTION[0002]Ulcerative colitis (UC) is a chronic intermittent and relapsing inflammatory bowel disease (IBD) of the colon characterized by superficial mucosal lesions that extend through the rectum and progress upstream. The natural history of UC is characterized by the progression of colonic lesions in up to 50% of subjects. This suggests that the colonic mucosa has a “global” susceptibility to environmental factors. Although genome-wide association studies have already identified more than 40 gene loci associated with UC, the primary defects initiating the cascade of events in colonic epithelial cells and leading to inflammation remain largely unknown. Recent data in animal models have shown that gut inflammation may be linked to an inability to manage the Unfolded Protein Response (UPR) in the epitheli...

Claims

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Application Information

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IPC IPC(8): C12Q1/68A61K31/429A61K31/47
CPCC12Q1/6876A61K31/429A61K31/47A61K31/155A01K2267/0325A01K67/02A61P1/04A61P43/00A01K67/0276A01K2227/10A01K2227/105A01K2267/03A61K49/0008C12N15/8509C12N2015/8527A01K2217/15
InventorOGIER-DENIS, ERICTRETON, XAVIERPEDRUZZI, ERICDANIEL, FANNY
OwnerINST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)