Venn Life Science and CEA host a workshop with European STEC-HUS experts : Jan 28th – 29th

On January 28th and 29th, Venn Life Sciences and its partner CEA (Pr. Daniel Gillet’s team) hosted a workshop gathering European experts on Hemolytic Uremic Syndrome caused by Shiga Toxin-producing Escherichia coli (STEC) contamination. Large STEC outbreaks and absence of specific therapies raise questions about the best options to treat patients. Supported and granted by the French National Research Agency (Agence Nationale de la Recherche – ANR) MRSEI action, the objective of this workshop was to start designing a new STEC-HUS management and evaluate how Retro 2.1, a broad-spectrum and host-directed molecule, can be used as a treatment for this indication.

Emerging STEC infections: a major concern for Europe

Since STEC recognition as a human pathogen in the 80’s, recurrent sporadic or seasonal outbreaks, small and large, also at the supranational level, keep being reported annually worldwide. The most important European outbreak remains the Germany crisis in 2011 that spread to other EU countries with 4,258 people infected with E. coli O104:H4 from whom 854 developed HUS and at least 54 died [1]. STEC infections are one of the most frequently reported zoonotic bacterial diseases (N= 6,378) after Campylobacteriosis (N=246,307), Salmonellosis (94,530) and Yersiniosis (N=6,861) (2016 data, [2]).

HUS: a severe and unpredictable complication impacting mainly children without therapy

E. coli O157:H7 strain is the main causal agent of STEC infections and HUS but strains belonging to other serogroups (O104, O26, O80) are more and more involved in severe outbreaks [3,4,5]. There are no good data indicating the incidence of STEC-HUS in Europe. All STEC have in common the production and release of Stx in the human intestine, causing the intestinal (diarrhoea, bloody diarrhoea, haemorrhagic colitis) and extra intestinal symptoms. About 15% of cases of infection progress towards HUS [6]. STEC are foodborne pathogens with a case-fatality rate relatively low, around 3 to 5% of HUS cases, but morbidity associated with kidney injury is significant. About 15% of patients with STEC-HUS progress to end stage renal disease (ESRD) within 4 years and about 25% have long term renal impairment [7,8].

Treatment of HUS is only supportive (fluid and mineral management, antihypertensive treatment, blood transfusions, treatment of neurological manifestations and renal replacement) [9]. Meta-analysis studies showed that using antibiotics to treat STEC infections is controversial and internationally not recommended because they increase the risk of HUS [10].

Besides, no treatment to impede HUS development is available [11]. Since 2000, several attempts to develop treatments or a vaccine to neutralize Stx were published. Some are still under development whereas others have failed to prevent HUS [12].

Retro 2.1, a small molecule developed by Daniel Gillet’s team could be a solution.

CEA with Institut Curie and INSERM succeeded in developing a lead candidate called Retro-2.1 [13-14]. This New Chemical Entity (NCE) has broad-spectrum inhibitory activities against intracellular toxins and pathogens (viruses, intracellular bacteria and parasites) that rely on syntaxin-5 to infect cells [15]. It is an inhibitor of the host trafficking pathway from early endosomes to the trans- Golgi network that is nevertheless remarkably non-toxic to cells. As a result, the drug blocks the retrograde trafficking and toxicity of Stx1 and Stx2 [16]. This approach can protect mice from E. coli O104:H4 infection (a model of STEC-HUS) [14], ricin intoxication [13], two viral infections (vaccinia, and enterovirus 71) and Leishmania (reviewed in [15]). In vitro, it can also protect cells from cholera toxin, filoviruses, Herpes viruses and Chlamydiales including the sexually transmitted Chlamydia trachomatis (reviewed in [15]).

European experts met to design another future for STEC-HUS management

On January 28thand 29th, with the support of an ANR MRSEI grant, a multidisciplinary team of experts (epidemiologists, clinicians, microbiologists, cell and structural biologists, pharmacologists and public health specialists) met at Venn Life Sciences in Paris to discuss the opportunity to reshape STEC-HUS management in Europe. Twenty persons coming from 12 different organizations1highlighted important issues as the absence of sufficient EU-harmonized surveillance, specific treatment, and the importance of early management of STEC-HUS. This meeting was also the opportunity to get feedback from experts on Retro 2.1 molecule as a potential candidate to prevent and treat STEC-HUS.

1, Gianluigi Ardissino (FONDAZIONE IRCCS CA’ GRANDA – OSPEDALE MAGGIORE POLICLINICO), Valentina Capone (FONDAZIONE IRCCS CA’ GRANDA – OSPEDALE MAGGIORE POLICLINICO), Petya Berger (WWU Münster), Maurizio Brigotti (University of Bologna), Ingrid Friesema (RIVM), Sebastian Loos (UKE), Jun Oh (UKE), Mickael Riou (INRA), Stefano Morabito (ISTITUTO SUPERIORE DI SANITA), Gaia Scavia (ISTITUTO SUPERIORE DI SANITA), Nicole van de Kar (Radboud University Medical Center), Eric Oswald (INSERM), Olena Pylypenko (Institut Curie), Isabelle Philippe (CEA), Daniel Gillet (CEA), Robin Vinck (CEA), Katsuhiro Mihara (Venn Life Sciences), Sabien van der Schoot (Venn Life Sciences), François Aubin (Venn Life Sciences), Carine La (Venn Life Sciences).

For more information, please contact Carine La: carine.la@vennlife.com

References:

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