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Analyse exploratoire des thérapies antisens innovantes dans le traitement des syndromes lymphoprolifératifs et autres maladies impliquant la lignée lymphoïde B

Abstract : Antisense oligonucleotides (ASO) can be used to direct some steps in mRNA maturation as splicing and polyadenylation in order to modulate gene expression. During lymphoid B-lineage development, maturation of immunoglobulin (Ig) transcripts involves alternative splicing and polyadenylation mechanisms. My thesis work has shown that ASO can be used to dissociate the two interconnected steps of transcription and splicing in order to study the sole impact of splicing of Ig germinal transcripts (GLT) during Ig class switch recombination. The submission of patent n°EP19305716.3 also allowed me to make a proof of concept for ASO usage to influence the polyadenylation of a specific Ig isotype by targeting the alternative polyadenylation sites (PAS) responsible for the production of membrane or secreted Ig. In fact, targeting the PAS used for the secreted IgE transcript with an ASO has made it possible to reduce IgE secretion and could be a new therapeutic strategy in IgE-dependent allergies. Finally, I developped a knock down method using splice switching oligonucleotide (SSO) that induces exon skipping during splicing and the appearance of alternative transcripts carrying a reading frameshift and a premature stop codon. This method could be used to target many genes expressed in eukaryotic cells, like B or plasma cells.Despite their limitations in terms of biodistribution, ASOs constitute innovative avenues for the development of new therapies against B lineage related diseases and lymphoproliferations.
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Anne Marchalot. Analyse exploratoire des thérapies antisens innovantes dans le traitement des syndromes lymphoprolifératifs et autres maladies impliquant la lignée lymphoïde B. Médecine humaine et pathologie. Université de Limoges, 2020. Français. ⟨NNT : 2020LIMO0030⟩. ⟨tel-03429598⟩

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