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

Background: Allergy regroups numerous complex and various diseases classified as IgE-dependent or non-dependent hypersensitivities. IgEs are expressed as membrane and secreted forms by B cells and plasma cells, respectively. In IgE-mediated hypersensitivity, IgE secretion and binding to high-affinity FcεRI on effector cells are responsible for the onset of allergic symptoms but in contrast, surface IgE expression as a B-cell receptor (BCR) is barely detectable. Objective: To test an innovative antisense approach to reduce IgE secretion. Methods: We designed an antisense oligonucleotide (ASO) targeting the polyadenylation signal (PAS) of human secreted IgE in order to redirect IgE transcript polyadenylation from the secreted form to the membrane form. ASO treatments were performed in B cells from transgenic mice expressing humanized IgE (InEps™), as well as human primary B cells and myeloma cells. In vivo ASO delivery was tested using the InEps™ model. Results: We demonstrated that treatment with morpholino ASO targeting the secreted IgE PAS drastically decreased IgE secretion and inversely increased membrane-IgE mRNA expression. In addition, ASO treatment induced apoptosis of IgE-expressing U266 myeloma cells, and RNA-seq revealed attenuation of their plasma cell phenotype. Remarkably, systemic administration of ASO coupled to Pip6a as an arginine-rich cell-penetrating peptide decreased IgE secretion in vivo. Conclusion: Altogether, this ASO strategy could be an effective way to decrease IgE secretion and allergic symptoms in patients suffering from IgE-dependent allergies, and could also promote allergen tolerance through apoptosis of IgE+ antibody-secreting cells.