Targeting the Splicing of mRNA in Autoimmune Diseases: BAFF Inhibition in Sjögren's Syndrome as a Proof of Concept
Year: 2013
Type: article
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.
Source: Molecular Therapy
DOI: 10.1038/mt.2013.275
Institutions: National Institutes of Health, Amsterdam UMC Location University of Amsterdam, National Institute of Dental and Craniofacial Research, Inserm, Hôpitaux Universitaires de Strasbourg, Hôpital d'Hautepierre, Immuno-Rhumathologie moléculaire, Université de Strasbourg, Centre National de la Recherche Scientifique, Institut de Myologie, Institut Cochin, Université Paris Descartes, Université Paris-Sud, Assistance Publique – Hôpitaux de Paris, Hôpitaux universitaires Paris Sud
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2073838891