Roescher N, Vosters J L, Alsaleh G, Dreyfus P, Jacques S, Chiocchia G, Sibilia J, Tak P P, Chiorini J A, Mariette X, Gottenberg Jacques-Eric
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.
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.
Mol Ther. 2014 Apr;22(4):821-7. doi: 10.1038/mt.2013.275. Epub 2013 Dec 5.
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.
BAFF（肿瘤坏死因子家族的B细胞激活因子）是B细胞激活的关键细胞因子，在原发性干燥综合征（pSS）中，唾液腺（SG）上皮细胞会过度表达该因子。ΔBAFF是BAFF的一种生理性抑制剂，是BAFF的一种次要可变剪接变体。重新设计了U7 RNA以递送靶向BAFF剪接区域的反义序列。在体外观察到BAFF信使核糖核酸（mRNA）和蛋白质分泌显著减少，同时ΔBAFF mRNA增加。在体内，将克隆到腺相关病毒载体中的修饰U7对非肥胖糖尿病小鼠进行SG逆行灌注，可显著降低BAFF蛋白表达和淋巴细胞浸润，并改善唾液分泌。本研究为pSS中局部治疗性抑制BAFF提供了理论依据，并代表了外显子跳跃在自身免疫性疾病中的应用原理证明。
