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Treatment of Ulcerative Colitis by Targeting Endoplasmic Reticulum Stress – CURRENT

-Change the paradigm to treat Ulcerative Colitis

The overall goal of our project is to explore new therapeutic strategies for the treatment of Ulcerative Colitis (UC), a chronic inflammatory bowel disease based on our recent results obtained from biopsies of patients with UC

Define a new therapeutic approache of UC

Current treatment of UC are not sufficient to control the disease in long term use as 25-30% of patients are in treatment failure. Our strategy was to compare the non-inflamed colonic mucosa of patients with UC compared to healthy controls in order to seek early abnormalities of mucosa, and develop a new mouse model reproducing the same clinical/ histological changes than UC. Our goal is to: 1)-offer a new therapeutic approach for UC based on understanding the early changes of the disease by targeting alterations of ER stress, 2)-evaluate the effectiveness of two drugs (Salubrinal and Guanabenz) likely to correct these alterations of ER stress, and prevent the development of colitis in animals. Prospects and immediate benefits of this project will be to develop new molecules similar to these two compounds to make them applicable to human.

Our experimental approach is based on the treatment of EXCY2 mice, which reproduce clinical characteristics of UC by two drugs modulating ER stress in preventive and curative protocols established in the laboratory. Preventive treatments of colitis are carried out over a period of three weeks in 3 week-old mice prior to the establishment of colitis. Curative treatments are carried out over a period of three weeks on 6-week-old mice with established colitis. Different doses and different frequency of injection of two drugs (Salubrinal Guanabenz) are tested alone or in combination with salicylates (5ASA) that constitute the current therapy of patient with UC.

We show that these two drugs exert an effective preventive effect on the onset of colitis after three weeks of treatment with 3 weekly injections. For the first time, we show that the use of compounds targeting a functional deficit of the colonic mucosa can prevent the onset of inflammation without changing the balance of the immune system. We are trying to develop derivatives of these molecules, which are devoided of toxicity in humans and may retain a preventive activity against colitis

Proof of concept of the preventive effect of Salubrinal and Guanabenz and curative effect in association with the 5ASA were established in a manner consistent with the predictions of the CURRENT project. The extension of the project to generate new molecules derived from Salubrinal and Guanabenz seems to be promising in terms of development and therapy.

In 2012 we filed a patent protecting mice developping UC and an international patent extension on the treatment of ulcerative colitis. We published in Gastroenterology (best journal of specialty) and a chapter in an encyclopedia is being published

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by a chronic, superficial and homogenous inflammation of the colonic mucosa. UC affects 35-100/100,000 individuals in North America and Northern Europe with an incidence of about 8-15 people/100,000. The clinical course is characterized by exacerbations and remissions and the medical management of UC is not yet curative. Our recent data have identified a defective endoplasmic reticulum (ER) stress-dependent pathway in unaffected colon epithelium of patients with UC. Based on these findings, we have recently developed the first mouse model that spontaneously expresses all clinical and histological characteristics of human UC which constitute the key point of this proposal.

The CURRENT proposal aims to strengthen the proof of concept of the pre-clinical efficacy of 2 modulators of the ER stress response (one approved by the FDA for hypertension indication, and the another one not yet approved by the FDA) in our pertinent validated mouse model of UC by several approaches including acute administration or chronic delivery systems.

Our preliminary results demonstrated that drugs are able to accurately block the commitment of the colitis without exacerbate cytotoxic or side effects in mice opening new avenues in the therapeutic management of UC.

The CURRENT project associates two Research Teams that have complementary expertise.
Partner 1 (INSERM U773) has strong basic and clinical expertise in the pathophysiology of UC and is expert in the field of ER stress, inflammation, translational research, and pre-clinical models,
Partner 2 (INSERM U843) has strong expertise in IBD, inflammation, in vivo permeability, and bacteria translocation,
Partner 3 (clinical Gastroenterology Unit Beaujon Hospital) is the reference Centre of the medical management of IBD in France and has strong expertise to conduct international clinical trials providing facilities to develop large clinical trials after convincing preclinical data, and
Partner 4 (INSERM-Transfert) is the technology transfer office support in charge of patents and exploitation rights of the CURRENT project.

The CURRENT project has adequate intellectual property protection through a patent filed in Mars 2011 by INSERM-Transfert (in progress). The valorisation of the data will be through the industrial transfer to target industrial companies in order to grant them an exclusive licence on INSERM patent rights for the treatment of UC.

In conclusion,
(i) this project will open a new therapeutic approach in UC at a deeper level than actual treatments do,
(ii) the present project proposes to offer a better quality of life associated to a reduction of the cost related to frequent hospitalisations, surgical treatments (colectomy) and
(iii) the project aim at treating defects upstream of the inflammation related to UC that favours colorectal cancer development on the long term.
Therefore it could decrease the risk of colitis-related colorectal cancer.

Project coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS VII (Divers public)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM-TRANSFERT
ASSISTANCE PUBLIQUE HOPITAUX DE PARIS - CENTRE HOSPITALIER UNIVERSITAIRE BEAUJON
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS VII
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PARIS VII

Help of the ANR 230,872 euros
Beginning and duration of the scientific project: November 2011 - 24 Months

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