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

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 (FceRIβ) to eliminate surface high-affinity IgE receptor (FceRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FceRIβ 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 FceRIβ is a potential approach for mast cell-specific treatment of allergic diseases.A sthma and related allergic diseases affect up to 1 in 10 people in developed countries, and about 10% of patients with asthma cannot be controlled with current therapeutic approaches. The most widely used therapies for asthma rely upon dampening the inflammatory response with either oral or inhaled glucocorticosteroids and relaxing the constricted airway smooth muscle cells with β-adrenoreceptor agonists. However, high doses of steroids when needed for severe asthma are associated with undesirable side effects and inhaled β-adrenoreceptor agonists can increase the risk of death from asthma if not used in combination with glucocorticosteroids. It is suggested that β-adrenoreceptor agonists may promote underlying inflammation that could contribute to the airway wall remodeling seen in asthma (1). Other clinical approaches that aim for more long-term alleviation of symptoms, including desensitization with incremental increases in dose of allergen or hyposensitization to induce immune tolerance, have proven beneficial for some, but not all, patients, and serious adverse effects can occur (2).In addition to asthma, other allergic diseases have similar treatment strategies and also have an unmet clinical need. An example is atopic dermatitis (AD), which like asthma, is also a multifactorial disease with complex pathophysiology, remains incurable, and affects 10-20% of children in the United States (3). The two major symptoms of AD are inflammatory lesions and severe pruritus. Both the prevalence and the economic burden of AD are increasing worldwide. Symptomatic treatment with topical and/or systemic glucocorticosteroids or calcineurin inhibitors are still considered the gold standard. However, due to the known adverse effects of these drugs, prescription rates are low and patient compliance is often poor (3). Thus, there is still a need for new therapeutic approaches with a better safety profile.An approach for intervention in allergic inflammation that we have pursued is based on the finding that the gene loci 11q12-q13 are strongly linked to allergy and asthma suscepti...

Basophil FcεRI Expression in Chronic Spontaneous Urticaria: A Potential Immunological Predictor of Response to Omalizumab Therapy

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Mast cells signal their importance in health and disease

“…In the first of these articles, a recently identified technique referred to as exon skipping has been specifically applied to target and downregulate IgE receptor expression on mast cells. 110 This approach affects specifically the mast cell/basophil compartment, unlike use of tyrosine kinase inhibitors that target receptors or pathways present in multiple cell types. This approach used antisense oligonucleotidemediated exon skipping of the b-subunit of FcεRI to eliminate surface expression of FcεRIb, which in turn eliminates surface expression of FcεRI.…”

“…This approach worked in vivo, as shown in mouse models of IgE-dependent allergic dermatitis. 110 Another novel approach depended on engineering a mechanism-based SCF partial agonist. 111 Normally, SCF is a growth factor that acts through KIT to promote hematopoietic progenitor cell expansion.…”

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

“…Morpholino oligomers bind mRNA and either block translation or modify pre-mRNA splicing and induce exon skipping ( 252 ). This approach has recently been demonstrated in mice showing that morpholinos targeting the FcεRI β-subunit decreased IgE receptor expression and function on mast cells and basophils ( 240 ) and was beneficial in treating a mouse model of allergic dermatitis. Morpholino-based therapy is approved for Duchenne muscular dystrophy ( 243 , 244 ), suggesting that this approach can succeed.…”