Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Targeting the Splicing of mRNA in Autoimmune Diseases: BAFF Inhibition in Sjgren's Syndrome as a Proof of Concept.

Roescher5,  Nienke, Vosters2,  Jelle L., Saleh6,  Ghada Al, Dreyfus7,  Patrick, Jacques4,  Sebastien, Garcia7,  Luis, Chiocchia4,  Gilles

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Academic Medical Center/University of Amsterdam
Bicetre Hospital
Cochin Hospital
National Institutes of Health, National Institute of Dental and Craniofacial Research
Strasbourg Hospital, EA 4438
UMR 7215 CNRS, Institut de Myologie


B-cell activating factor of the TNF family (BAFF) is a relevant target in autoimmunity. BAFF is increased in various animal models of autoimmunity and in patients with autoimmune diseases, including Sjögren's syndrome (SjS). Moreover, inhibition of BAFF using monoclonal antibodies or soluble receptors improves the course of arthritis, diabetes, and systemic lupus erythematosus in animal models of autoimmunity. There are as yet no data available regarding the efficacy of BAFF inhibition on salivary gland (SG) inflammation and dysfunction in animal models of SjS.

Delta BAFF is a physiological non-secreted inhibitor of BAFF. It prevents the intracellular binding of BAFF to other monomers of BAFF and APRIL, another important factor in the activation and survival of B cells, and inhibits BAFF secretion. Delta BAFF is a splice variant of BAFF and lacks a single exon compared with full length BAFF (exon 3 in humans, exon 4 in mice), which is naturally more abundant than delta-BAFF.

The use of exon skipping to promote the expression of one shorter variant over the predominant full length mRNA has shown encouraging effects for the treatment of the monogenic disease Duchenne's myopathy and offers exciting therapeutic opportunities for many other diseases. We hypothesized that targeting the splicing of BAFF mRNA using exon skipping and thereby decreasing BAFF may improve features of SjS.


Adeno-associated virus (AAV) and lentiviral vectors were constructed encoding U7 RNA with an antisense sequence targeting the exon of BAFF, which is absent in delta-BAFF. The expression of BAFF and delta-BAFF mRNA was assessed by PCR after infection of U937 and human lymphoma cell lines.

Exon skipping-inducing AAV (AAV 161) or an AAV control vector encoding for beta galactosidase (LacZ) were administered by retrograde canulation of the submandibular glands of 19 NOD mice at the age of 10 weeks. Salivary gland function was assessed and expression of BAFF and SG inflammation was determined by quantitative immunohistochemistry 10 weeks post-treatment.


In vitro transfection of U937 and human lymphoma cell lines with an exon skipping inducing lentivirus resulted in a marked decrease of BAFF and an increase of delta-BAFF mRNA and decreased BAFF protein in the supernatant.

In vivo, BAFF expression in the SG was significantly decreased (48% decrease in optical density per mm2, p<0.05) in mice treated with AAV161. Stimulated saliva flow increased with almost 100% from 2.0 (control LacZ mice) to 3.8 (AAV161) ul/20min/gram body weight, p<0.01. In addition, treatment with AAV161 decreased the average number of salivary gland lymphocytic infiltrates per cross sectional surface area of the SG (3.9 vs 2.4, p<0.05) and reduced the number of B (D87%, p<0.05) and plasma cells (D69%, p<0.01), compared with control mice.


These results demonstrate the efficacy of BAFF inhibition on features of SjS in NOD mice and offer a rationale to evaluate BAFF inhibition in patients with SjS. This study also represents a proof of concept of the efficacy of modulating mRNA splicing in autoimmune diseases.

To cite this abstract, please use the following information:
Roescher, Nienke, Vosters, Jelle L., Saleh, Ghada Al, Dreyfus, Patrick, Jacques, Sebastien, Garcia, Luis, et al; Targeting the Splicing of mRNA in Autoimmune Diseases: BAFF Inhibition in Sjgren's Syndrome as a Proof of Concept. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1413
DOI: 10.1002/art.29179

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