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NOVEL THERAPY FOR ASTHMA AND ALLERGIC RHINITIS THROUGH GENE SILENCING OF CD40 USING SMALL INTERFERING RNA

University of Western Ontario, London, ON, Canada

PURPOSE: Small interfering RNA (siRNA) is a potent, selective, and easily-inducible method for specifically blocking expression of desired genes. siRNA is reported to be more efficient than traditional therapy such as antisense oligonucleotides. However, the therapeutic potential of siRNA for allergic diseases has not yet been investigated. CD40 is an important costimulatory molecule that plays a critical role in allergic responses. In this study, we attempted to develop a potential new therapy for asthma and allergic rhinitis through silencing the expression of CD40 using siRNA.

METHODS: Mice were sensitized with a mixture of ovalbumin (OVA) and alum, and challenged with OVA after administration of a siRNA expressing vector specific to CD40 (CD40 siRNA), control vector expressing scrambled siRNA (control siRNA) as negative control, or PBS alone as another negative control.

RESULTS: Therapy with CD40 siRNA reduced CD40 expression in dendritic cells of the spleen (P<0.01), remarkably reduced allergic symptoms (P<0.01), and decreased eosinophilia in nasal and lung tissues (P<0.01), when compared with control siRNA or PBS alone. CD40 siRNA significantly reduced levels of interleukin-4 (IL-4) and interleukin-5 (IL-5) (P<0.01), and the number of eosinophils in the bronchoalveolar lavage fluid (BALF) (P<0.01). The OVA-specific T cell response was inhibited after therapy with CD40 siRNA (P<0.01). Additionally, anti-OVA specific IgE and IgG1 were significantly decreased in sera of mice that received CD40 siRNA therapy (P<0.01). In contrast, anti-OVA specific IgG2a did not change. The production of IL-4 and IL-5, but not interferon-gamma, by spleen and peribronchial lymph nodes were suppressed in mice which received CD40 siRNA (P<0.01). Finally, CD40 siRNA therapy facilitated the generation of regulatory T cells, in particular, the CD4+CD25+Foxp3+ subset of cells (P<0.01).

CONCLUSION: This study, for the first time, has demonstrated that therapy with siRNA specific to CD40 can reduce allergic responses and also attenuate asthma and allergic rhinitis.

CLINICAL IMPLICATIONS: Silencing CD40 gene expression by siRNA is a novel and effective therapy for the control of asthma and allergic rhinitis.

DISCLOSURE: Motohiko Suzuki, No Financial Disclosure Information; No Product/Research Disclosure Information