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Impact des immunoglobulines tronquées produites par saut d’exon dans les plasmocytes : vers des approches thérapeutiques utilisant des oligonucléotides antisens

Abstract : The thesis projects aimed to explore the therapeutic value of antisense approaches targeting immunoglobulin (Ig) transcripts in the treatment of multiple myeloma (MM) and other monoclonal gammopathies. This strategy consists in inducing an exon skipping using antisense oligonucleotides (ASO) to provoke the synthesis of truncated Ig and apoptosis of tumor plasma cells (Patent WO 2017/089359). The toxic effect V domain-less Ig is the consequence of an uncontrolled amplification of ER stress and the UPR (Unfolded Protein Response). We have shown that treatments with ASO directed against monoclonal Ig (mo-Ig) pre-mRNAs induced strong toxicity on myeloma cell lines and regression of tumor xenografts after intratumoral ASO injections. Although improvements in terms of in vivobiodistribution of ASOs are necessary, this approach capable of specifically destroying the tumor clone could allow a personalized treatment of MM patients and spare healthy plasma cells. We have also observed a drastic decrease in Ig production after treatment of stimulated human B cells or myeloma cells with a generic ASO targeting the exon CH1γ that can be used in all patients expressing IgG. In parallel, we explored the relationship between protein stress and RNA surveillance in plasma cells. In contrast with previously published data from non-lymphoid cells, we have demonstrated a cooperation between the mechanism of NMD (Nonsense-Mediated mRNA Decay) and UPR in plasma cells, favored by the low activation of the PERK pathway of the UPR. Therefore, these works have shed new light on the impact of truncated Ig in antibody-secreting cells and, on the close link between the proteic stress associated with massive Ig synthesis and plasma cell survival.
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Jean-Marie Lambert. Impact des immunoglobulines tronquées produites par saut d’exon dans les plasmocytes : vers des approches thérapeutiques utilisant des oligonucléotides antisens. Médecine humaine et pathologie. Université de Limoges, 2020. Français. ⟨NNT : 2020LIMO0029⟩. ⟨tel-03429593⟩

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