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Mécanismes moléculaires impliqués dans l’efficacité de transduction des vecteurs AAV dans le muscle dystrophique

Abstract : Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin and causing severe muscle degeneration. No curative treatment exists today but AAV-based gene therapy is one of the most promising strategies for treating DMD. Despite the well-established efficacy of AAV serotype 8 (AAV8) for gene transfer into muscle, high doses of vectors are required to achieve therapeutic efficacy in DMD animal models. In this context, I aimed at investigating the mechanisms that may limit the transduction efficiency of the AAV8 vector in dystrophic muscle. For this, I studied the fate of the AAV vector in the DMD muscle and then characterized the endosomal system, essential for the transport and maturation of AAV vectors, in different models of DMD. We have shown that the transduction efficiency of AAV8 is lower in DMD muscle cells compared to controls. The dysfunction of the endosomal system identified in this study may impact AAV vector gene transfer into these cells. Moreover, improving the efficiency of AAV vectors in gene therapy also requires a better understanding of cellular proteins that interact with the viral genome and regulate its expression. In this context, we have shown that the transcription factors RFX1 and RFX3 are able to interact with the ITR region of the viral genome and to modulate the expression of AAV vectors.
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Submitted on : Wednesday, October 13, 2021 - 1:01:41 AM
Last modification on : Tuesday, November 16, 2021 - 4:42:39 AM


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  • HAL Id : tel-03375648, version 1


Julie Chassagne. Mécanismes moléculaires impliqués dans l’efficacité de transduction des vecteurs AAV dans le muscle dystrophique. Biologie moléculaire. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS514⟩. ⟨tel-03375648⟩



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