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ANR funded project

Innovation biomédicale (DS0404) 2014
Projet AntiHUS

In vivo proof of concept of molecules against hemolytic uremic syndrome

Shiga toxin-producing Escherichia coli (STEC) infections affect hundreds of thousands of people annually in industrialized countries, including approximately 265,000 people in the United States according to the US Centers for Disease Control and Prevention (CDC). In 50% of people that experience Shiga toxin (Stx)-mediated events, clinical outcomes include hemorrhagic colitis, hemolytic anemia, thrombocytopenia, kidney failure, brain damage, Hemolytic Uremic Syndrome (HUS) and, for 3% to 5% of the latter patients, death. STEC is the principal cause of HUS, a life-threatening condition that appears more frequently in children and is the most common cause of acute renal failure in these patients. There is no approved treatment for STEC infections, and numerous antibiotics have been shown to increase the risk and severity of Shiga toxin-mediated events.

We identified compounds acting as inhibitors of the retrograde route used by toxins to enter into cells (Stechmann et al., Cell 2010). These patented compounds selectively block the intracellular transport of toxins from plant (ricin) and pathogenic bacteria (Stx), and one of these compounds (Retro-2) protects mice against lethal challenges by ricin. Our preliminary data, presented in this project, demonstrate that Retro-2 treatment improves survival of mice exposed to Shiga toxin. Moreover, the chemical optimization of the Retro-2 scaffold has led to a new compound, termed Retro-2.1, that is five hundred fold more active in vitro against Stx than Retro-2, and for which a new patent was filed.

Based on promising preliminary results, we propose to study the in vivo proof of concept of our patented molecules against HUS using a mouse model of E. coli infections. Such a study may result in a new therapeutic concept for the treatment of STEC infections and to the industrial development of a drug by a pharmaceutical company.

Partners

CEA CEA/DSV/IBITEC-S/SIMOPRO

IC INSTITUT CURIE - SECT DE RECHERCHE

INSERM UMR1043 Centre de Physiopathologie de Toulouse Purpan

ANR grant: 298 515 euros
Beginning and duration: octobre 2014 - 24 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE16-0004

Project coordinator:
Monsieur Julien Barbier (CEA/DSV/IBITEC-S/SIMOPRO)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.