Targeting IgE polyadenylation signal with antisense oligonucleotides decreases IgE secretion and plasma cell viability

Marchalot, Anne; Horiot, Catherine; Lambert, Jean-Marie; Carrion, Claire; Oblet, Christelle; Pollet, Justine; Cogné, Michel; Moreau, J.; Laffleur, Brice; Delpy, Laurent

doi:10.1016/j.jaci.2021.09.039

Cited by 9 publications

(6 citation statements)

References 24 publications

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“…The main advantage of our strategy is that it can specifically inhibit the secretion of a particular HC isotype while largely sparing humoral immunity. We have previously demonstrated the value of this approach for inhibiting IgE secretion in allergy (Marchalot et al, 2021). Approaches specifically targeting the secretion of an HC isotype are also of great interest in clinical manifestations due to polyclonal Ig such as autoimmune diseases, IgA nephropathy or acute graft rejection.…”

Section: Discussionmentioning

confidence: 99%

“…Antisense oligonucleotides (ASOs) are short single strand of modified DNA that can be used as “gapmer ASOs” to degrade RNA by RNAse H1 recruitment, or as “steric blocker ASOs” to modify RNA maturation processes such as splicing or polyadenylation, depending of the oligonucleotide chemistry (Bennett, 2019). In the lab, we previously used steric blocker ASOs to modify Ig expression in B-lineage cells (Ashi et al, 2018; Marchalot et al, 2020, 2021). Here, we assessed the impact of an ASO-mediated decrease in HC expression in IgG-expressing myeloma cells.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Horiot,

Roussel,

Praité

et al. 2023

Preprint

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Multiple myeloma (MM) is related to the accumulation of malignant plasma cells (PCs) in the bone marrow. MM accounts for approximatively 10% of hematological malignancies and despite major improvement in therapies and outcomes, relapses will virtually occur in all patients. Usually, the disease goes along with an excess production of a monoclonal immunoglobulin (Ig) component by the tumor PC clone. However, many questions remain regarding the consequences of a deregulated Ig production on PC survival. Recent advances in RNA-based therapy using antisense oligonucleotides (ASO) prompted us to examine the impact of altered Ig heavy to light chain (HC/LC) ratios in MM cells. We designed a pan IgG subclasses specific ASO targeting a consensus sequence found in the polyadenylation signal (PAS) of all secreted IGHG mRNAs (IgG-ASO). Remarkably, treatment with this compound strongly decreased IgG secretion in MM cell lines and patient cells. Consistent with a deregulated HC/LC ratio, a dose-dependent excess of free-LCs (as monomers and dimers) was observed in myeloma cells treated with IgG-ASO, compared to an irrevelant control ASO (CTRL). RNA-seq profiles further indicated that the expression of genes involved in cellular metabolism, unfolded protein response (UPR) and cell death pathways were altered after treatment with IgG-ASO. Interestingly, impaired survival of primary IgG-expressing cells isolated from MM patients was achieved upon treatment with IgG-ASO, whereas no major effect was observed for healthy cells. Altogether, our data provide evidence for efficient inhibition of IgG secretion upon ASO treatment and suggest that an excess of free-LC due to disruption of HC/LC stoichiometry is toxic for MM cells expressing complete Ig. Such RNA-based strategies targeting PC in an Ig isotype-dependent manner could open new avenues for selective therapeutic approaches in PC dyscrasias.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Horiot,

Roussel,

Praité

et al. 2023

Preprint

Self Cite

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“…In recent decades, RNA-based therapeutics have emerged as a promising avenue for treating various diseases, including metabolic disorders, ,, hematological diseases, − infectious diseases, − and cancers. − However, it is of significant importance to expand RNA therapeutics in orphan diseases. Orphan diseases encompass a diverse group of disorders that individually affect a small portion of the population.…”

Section: Chemical Modification-assisted Better Rna Therapeuticsmentioning

confidence: 99%

Chemically Modified Platforms for Better RNA Therapeutics

Shi,

Zhen,

Zhang

et al. 2024

Chem. Rev.

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RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration. CONTENTS1. Introduction 930 2. Current Status and Challenges of RNA Therapeutics in Clinics 933 2.1. Molecular Mechanisms and Clinical Research Progress of RNAs 934 2.1.1. ASO 934 2.1.2. siRNA 934 2.1.3. Aptamer 936 2.1.4. mRNA 936 2.1.5. RNA Therapeutics on the Cusp of Clinical Breakthroughs 938 2.2. Major Challenges of Current RNA Therapeutics in Clinics 940 2.

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“…Such a situation can occur in IgE-mediated allergies that are caused by an increased proportion of secreted versus membrane-bound isoforms of IgE, which differ in their polyadenylation sites 40 . Morpholino ASOs targeting the polyadenylation signal of IgE that are coupled to Pip6a, an arginine-rich cell-penetrating peptide, alter IgE transcript polyadenylation to produce more membrane-bound isoform and less secreted isoform.…”

Section: Nbts For Protein Upregulationmentioning

confidence: 99%

“…4 ). The change in IgE isoform composition may be beneficial for the reduction of IgE-related allergic symptoms and could promote allergen tolerance through apoptosis of IgE + antibody-secreting cells 40 .…”

Section: Nbts For Protein Upregulationmentioning

confidence: 99%

Amplifying gene expression with RNA-targeted therapeutics

Khorkova

Stahl

Joji

et al. 2023

Nat Rev Drug Discov

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Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

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Targeting IgE polyadenylation signal with antisense oligonucleotides decreases IgE secretion and plasma cell viability

Cited by 9 publications

References 24 publications

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Chemically Modified Platforms for Better RNA Therapeutics

Amplifying gene expression with RNA-targeted therapeutics

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