Targeting the Splicing of mRNA in Autoimmune Diseases: BAFF Inhibition in Sjögren's Syndrome as a Proof of Concept
| Autor: | PP Tak, Patrick A. Dreyfus, Sébastien Jacques, Gilles Chiocchia, Jelle L. Vosters, Nienke Roescher, John A. Chiorini, Jean Sibilia, Ghada Alsaleh, Xavier Mariette, Jacques-Eric Gottenberg |
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| Přispěvatelé: | Medical Microbiology and Infection Prevention, Clinical Immunology and Rheumatology |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_treatment
RNA Splicing Biology Lymphocyte Activation Exon Mice stomatognathic system Mice Inbred NOD immune system diseases RNA Small Nuclear B-Cell Activating Factor Drug Discovery medicine Genetics Animals Humans RNA Messenger B-cell activating factor skin and connective tissue diseases Molecular Biology Pharmacology Messenger RNA B-Lymphocytes Alternative splicing Exons Dependovirus Exon skipping stomatognathic diseases Cytokine Sjogren's Syndrome Immunology RNA splicing Molecular Medicine Tumor necrosis factor alpha Original Article |
| Zdroj: | Molecular therapy, 22(4), 821-827. Nature Publishing Group |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2013.275 |
| Popis: | BAFF (B-cell–activating factor of the tumor necrosis factor family), a pivotal cytokine for B-cell activation, is overexpressed by salivary gland (SG) epithelial cells in primary Sjogren's syndrome (pSS). ΔBAFF, a physiological inhibitor of BAFF, is a minor alternative splice variant of BAFF. A U7 RNA was reengineered to deliver antisense sequences targeting BAFF splice regions. A major decrease of BAFF messenger RNA (mRNA) and protein secretion, concomitantly with the increase of ΔBAFF mRNA, was observed in vitro. In vivo, SG retrograd instillation of nonobese diabetic mice by the modified U7 cloned into an adeno-associated virus vector significantly decreased BAFF protein expression and lymphocytic infiltrates and improved salivary flow. This study offers a rationale for localized therapeutic BAFF inhibition in pSS and represents a proof of concept of the interest of exon skipping in autoimmune diseases. |
| Databáze: | OpenAIRE |
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