Team "Biotherapy" : Biotherapies by vectorization of nucleic acids

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RESEARCH THEMES

 1-Development of interfering RNA vectorization strategies for the treatment of hepatic fibrosis
Non-alcoholic steato-hepatitis (NASH) is a multifactorial chronic hepatopathy with an increasing prevalence in the world that leads progressively to hepatic fibrosis, which can elicit cirrhosis or hepatocellular carcinoma. None of current anti-fibrosis treatments seem very convincing in clinical studies. It is therefore necessary to propose new therapeutic strategies, and the use of small interfering RNAs is of major interest in this context. Within the team, we have set up a metabolic model of hepatic fibrosis, induced by a specific diet deficient in essential amino acids. The interest of this model is that the establishment of fibrosis follows more faithfully the evolution of a metabolic disease observed in human NASH, with induction of steato-hepatitis and fibrosis. In this model, therapeutic strategies based on siRNAs will be implemented by adapting existing self-assembled nanoparticle-type vectors to make them more efficient, less toxic and more specific to the liver cells targeted, in particular the stellate cells. Follow-up of fibrosis markers will be an essential part of this project to evaluate the effectiveness of the therapeutic strategy. In addition to conventional follow-up, other methods are considered, such as the morphological characterization of collagen fibers on liver cuts by multiphotonic imaging (Collaboration with the Imaging Department of the Institut Pasteur) or non-invasive imaging of liver fibrosis by magnetic resonance elastography (Collaboration with CNRS-CREATIS UMR5220, Lyon). When phenotyping the model of hepatic fibrosis in mice, we demonstrated the presence of an atypical population of stellate cells, characterized by an exacerbated intracellular storage of retinoids. We have shown that this phenomenon of stellate cell hypertrophy is not limited to this metabolic model since it is also present in other models, metabolic or toxic, of fibrosis in mice, and especially that it can be observed in biopsies from patients with hepatic fibrosis. In addition, we have demonstrated a positive correlation between the degree of hypertrophy and the stage of fibrosis. The discovery of the existence of this atypical stellate cell phenotype in a context of fibrosis opens up new avenues for the study of this pathology and in particular the possibility of identifying new therapeutic targets.

 2-Genetic immunization
The objective of this project is to design strategies for vectorization of mRNA in vaccine applications against infectious diseases. The antigen against which the immune response is sought is encoded in the mRNA molecule transcribed in vitro or IVT-mRNA. Vectorization strategies are necessary to enable access of the mRNA to the cellular machinery, allowing the in situ production of the antigen and the onset of the immune response against it. mRNA does not require to be transported to the nucleus, unlike plasmid DNA, since mRNA is processed in the cytoplasm. We intend to formulate IVT-mRNA molecules in our self-assembled nanoparticle-type vectors and to administer them according to different routes of administration in order to evaluate the humoral and cellular immune response induced by the expression of the antigen encoded by the IVT-mRNA. Two vaccine applications are envisaged: (i) immunization against Chagas disease in collaboration with Dr Alonso-Padillala and Pr Gascón, University of Barcelona, (ii) Immunization against gestational malaria in collaboration with Dr Ndam with the MERIT laboratory "Mother and child with tropical infections", IRD, Université de Paris.

 3- Compression of pharmaceutical carriers containing siRNAs for oral administration
Oral route is currently the most widely used route of drug administration because of its ease of use combined with good patient compliance. However, the routes of administration of vectorized nucleic acids are most often local or i.v. injection. Thus, formulations for oral administration containing siRNAs have an important potential for the development of novel therapeutics. This project is based on preliminary results obtained recently in collaboration with the team of Pr Tchoreloff (CNRS UMR 5295 Bordeaux). We have shown that it is possible to formulate siRNA vectors in tablets and to preserve the gene silencing efficiency of the particle and have filed a patent describing these controlled steps and processes. Following the preliminary steps of in vitro assays, in vivo evaluation both in terms of biodistribution and effectiveness on a disease model (ulcerative colitis induced by dextran sulfate) will be conducted in rodents to which solid formulations of siRNA particles will be administered orally


 4- Penetrating and interfering peptides for the treatment of cancer
This project is based on the modeling, characterization and development of new therapeutic tools intended for the treatment of cancers with high medical needs in terms of specificity and side effects. To this end, we use the approach of tumoral penetrating and interfering peptides (TP and IP), that are able to specifically penetrate into the tumor cell, without effect on healthy cells and blocking the interaction between two proteins deregulated in tumor transformation. We are also developing organelle-specific penetrating peptides primarily focused on the nucleus and mitochondria.
The approach of cell penetrating and interfering peptides has great relevance in medicine since more than 240 therapeutic peptides are currently being tested in clinical trials. In addition, a high number is already approved for the treatment of several pathologies. This project is of great relevance in the field of oncology and original in terms of the approach used to identify protein / protein interactions as well as the optimization of drug candidates.
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