title: Targeting the splicing of mRNA in autoimmune diseases: BAFF inhibition in Sjögren's syndrome as a proof of concept.
abstract: 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.
authors.affiliation: 1] Division of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands [2] Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: N
authors.initials: N
authors.lastname: Roescher
authors.affiliation: 1] Division of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands [2] Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Vosters
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Faculté de Médecine Université de Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Fédération de Médecine Translationnelle de Strasbourg, Service de Rhumatologie, Hôpital Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Strasbourg, France.
authors.forename: G
authors.initials: G
authors.lastname: Alsaleh
authors.affiliation: UPMC Um76, Inserm U974, CNRS UMR7215, Institut de Myologie, 105 Bd de l'Hôpital, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Dreyfus
authors.affiliation: Inserm, U1016; Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Jacques
authors.affiliation: Inserm, U1016; Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Chiocchia
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Faculté de Médecine Université de Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Fédération de Médecine Translationnelle de Strasbourg, Service de Rhumatologie, Hôpital Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Strasbourg, France.
authors.forename: J
authors.initials: J
authors.lastname: Sibilia
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Chiorini
authors.affiliation: Université Paris-Sud; INSERM U1012; AP-HP, Hôpitaux universitaires Paris-Sud; Le Kremlin Bicêtre, France.
authors.forename: X
authors.initials: X
authors.lastname: Mariette
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Faculté de Médecine Université de Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Fédération de Médecine Translationnelle de Strasbourg, Service de Rhumatologie, Hôpital Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Strasbourg, France.
authors.forename: Jacques-Eric
authors.initials: JE
authors.lastname: Gottenberg
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus; D005091:Exons / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics*; D012342:RNA, Small Nuclear / Q000235:genetics; D012859:Sjogren's Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: D053264:B-Cell Activating Factor; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; C505720:Tnfsf13b protein, mouse; C405487:U7 small nuclear RNA