Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Published online before printNovember 21, 2016, doi:10.1073/pnas.1608520113 PNAS November 21, 2016

1. Glenn Crusea,b,1, 
2. Yuzhi Yinb, 
3. Tomoki Fukuyamaa, 
4. Avanti Desaib, 
5. Greer K. Arthura, 
6. Wolfgang Bäumera,
7. Michael A. Beavenc, and 
8. Dean D. Metcalfeb

Author Affiliations

1. Edited by K. Frank Austen, Brigham and Women's Hospital, Boston, MA, and approved October 26, 2016 (received for review May 27, 2016)

1. Abstract
2. Full Text
3. Authors & Info
4. Figures
5. SI
6. Metrics
7. Related Content
8. PDF
9. PDF + SI

Significance

We identified an innovative use for the technique of antisense oligonucleotide-mediated exon skipping to specifically target and down-regulate IgE receptor expression in mast cells. Exon skipping is typically used as part of personalized medicine, where a mutant exon is skipped after sequencing the patients’ affected genes. Our approach, however, targets a nonmutated gene and an exon that is critical for surface IgE receptor expression. It does not require a personalized approach with genetic sequencing or multiple iterations of oligonucleotides that would require clinical trials. Furthermore, the diseases to be treated with this technology are ideal for local delivery of the oligonucleotides by aerosols or topical cream formulations.

Abstract

Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FcεRIβ) to eliminate surface high-affinity IgE receptor (FcεRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FcεRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FcεRIβ is a potential approach for mast cell-specific treatment of allergic diseases.

1. PDF
2. PDF + SI