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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.

Original publication

DOI

10.1038/mt.2013.275

Type

Journal

Mol Ther

Publication Date

04/2014

Volume

22

Pages

821 - 827

Keywords

Animals, B-Cell Activating Factor, B-Lymphocytes, Dependovirus, Exons, Humans, Lymphocyte Activation, Mice, Mice, Inbred NOD, RNA Splicing, RNA, Messenger, RNA, Small Nuclear, Sjogren's Syndrome