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Traitement de l’hémophilie A à l’aide d’ARNm codant le facteur VIII et prévention de la réponse immunitaire dirigée contre le facteur VIII thérapeutique

Abstract : Hemophilia A is a rare hemorrhagic disease due to a lack of functional pro-coagulant factor VIII (FVIII). Severe hemophilia A causes spontaneous bleeding and can even lead to death. The prevention and treatment of hemorrhages is achieved by injection of therapeutic FVIII. This treatment is however complicated by its exorbitant cost and the short half-life of FVIII, hampering the patients’ quality of life. Moreover, in 25 to 35% of the patients, the infusion of exogenous FVIII induces the development of anti-FVIII antibodies which inhibit its pro-coagulant activity and are called “FVIII inhibitors”. During my PhD, I first validated in vivo a new therapeutic strategy, alternative to the actual replacement therapy, using a FVIII-encoding mRNA (Article 1). In the second part, I assessed the possibility to inhibit the anti-FVIII immune response by inhibition of B lymphocytes. To do so, I used an inhibitor of Bruton’s tyrosine kinase (Btk), a kinase involved in the signalling pathway of the receptor of B cells (BCR)(Article 2). Finally, I characterized an hemophilia A mouse model, humanized for MHC. This model lacks FVIII as well as mouse MHC class I and II expression and is transgenic for human MHC I and II. The results obtained during my PhD validate the use of in vitro transcribed mRNA technology for hemophilia A treatment. They also provide a new strategy to inhibit the memory immune response against FVIII and describe a novel mouse model for studying anti-FVIII immune responses.
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Jules Russick. Traitement de l’hémophilie A à l’aide d’ARNm codant le facteur VIII et prévention de la réponse immunitaire dirigée contre le facteur VIII thérapeutique. Immunologie. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS362⟩. ⟨tel-02865552⟩

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