Une nouvelle stratégie de traitement de la maladie cœliaque basée sur les polymères séquestrants

Celiac Disease or celiac sprue is identified as a gluten intolerance. It is an inflammatory disorder of the intestine triggered by the ingestion of gluten in genetically susceptible individuals. This condition is highly prevalent because it affects up to 1% of the worldwide population. Nowadays, there is no pharmacological treatment available to treat or off set to the disease. Due to the huge progress in the understanding of the pathogenesis, new therapeutic targets have been discovered. At the present time, the only effective treatment remains the strict lifelong abandonment of the pathogen agent, gluten. Gluten encompasses the storage proteins in wheat, rye and barley. The wheat gluten is divided into glutenins and gliadins. The latter seem to be the most important trigger in the celiac disease. Gliadins and the related proteins (i.e. secalins and hordeins, respectively in rye and barley) are rich in prolin and glutamin residues, conferring them to be resistant by enzymatic digestion. The resulting peptides of the incomplete process may set off the inflammatory reaction. The main objective of this thesis was to test a new supportive therapy in treating celiac disease, useful in punctual occasion (i.e. during travel or social event when the gluten-free property cannot be ascertained).  In the 1980’s, inhibition of some gliadin-induced effects on cell cultures were observed owing to mannan co-incubation. However, this compound, due to his osidic nature, may be cleaved by digestive enzymes in vivo. Synthetic polymers prove to be an attracting alternative owing to the tunability of their physical and chemical properties. The goal of this study was to obtain a polymeric gliadin-binder, interferring with the pathogenesis of the celiac disease in the gastro-intestinal tract, to abrogate the gliadin induced effects.  Atom transfer radical polymerization was used to synthesize copolymers of the type poly (hydroxyethylméthacrylate)-co-(styren sulfonate) (P(HEMA-co-SS)). A small library of polymers varying in their molecular weight and in their constituting monomers ratio was prepared. The ability of these polymers to sequester gliadin was assessed at stomacal and intestinal pH. The best candidates were further evaluated in cell cultures. Our results revealed that a selective binding was obtained with the P(HEMA-co-SS) (45:55 mol%, 40 kDa). This compound abolished gliadin-induced effects on various cell lines. In addition, gliadin digestion was hindered, suggesting a decrease in the formation of immunogenic peptides known to trigger the diseases. In vivo experiments were additionally carried out on a murine model of gluten-sensitivity with this polymeric candidate. Its efficacy towards pure gliadin and gluten containing food was tested. P(HEMA-co-SS decreased gliadin–induced effect on permeability and inflammatory parameters and modulated the immune response due to gliadin/gluten gavage. Toxicity and biodistribution studies following acute and chronic administration were performed on murine to demonstrate that the polymer was well tolerated and not absorbed after oral administration. Finally, biopsies of patients suffering from CD disease exhibited therapeutic benefit of the polymer.  Altogether, the results presented in this thesis evidenced the potential of P(HEMA-co-SS) to prevent the gluten-induced disorder, indicating that this type of polymer may be useful in a near future.

Keyphrases: Gluten, Polymeric binders, Gluten, Celiac disease, Gliadin