The exon-skipping oligonucleotide, KitStop, depletes tissue-resident mast cells in vivo to ameliorate anaphylaxis

Abstract Anaphylaxis represents the most extreme, life-threatening form of allergic disease and is often an emergency requiring immediate intervention. It occurs following cross-linking of the high-affinity IgE receptor (FcɛRI) on the surface of mast cells by allergen-IgE complexes; however, non-IgE-mediated and idiopathic mast cell activation also contribute. Causes include environmental allergens, foods, venoms, and medications. In addition, some people with mastocytosis have repeated anaphylactic episodes during normal daily activities with no exposure to these triggers. While acute therapy consists primarily of epinephrine and supportive care, chronic therapy relies heavily on desensitization to the inciting allergen—a time-consuming and sometimes unsuccessful process. Desensitization also requires identification of the trigger which is not always possible. Here, we report the use of an exon-skipping oligonucleotide, previously termed KitStop, to safely reduce the severity of anaphylaxis via mast cell depopulation in tissues. KitStop administration results in the integration of a premature stop codon within the mRNA transcript of the Kit receptor—a receptor tyrosine kinase found primarily on mast cells and whose gain-of-function mutation can result in systemic mastocytosis. After either local or systemic KitStop treatment, mice had significantly reduced mast cell numbers in the skin, peritoneum, and lungs. In addition, KitStop-treated mice had a significantly diminished anaphylactic response in a model of passive systemic anaphylaxis. These data demonstrate that KitStop has the potential to serve as a powerful treatment option for patients that experience anaphylaxis, including idiopathic anaphylaxis. Research was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Award Number R01AI143985 (G.C.), Department of Molecular Biomedical Sciences, College of Veterinary Medicine, start-up funds (G.C.), NCSU Center for Human Health and the Environment NIH P30ES025128 (G.C.), Institutional National Research Service Award from the Office of the Director of National Institutes of Health, NIH T32OD011130 (B.H., D.S.).