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

Autor:	Hedgespeth BA; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States.; Department of Clinical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States.; Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.; Comparative Medicine and Translational Research Training Program, North Carolina State University, Raleigh, NC, United States., Snider DB; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States.; Department of Clinical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States.; Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.; Comparative Medicine and Translational Research Training Program, North Carolina State University, Raleigh, NC, United States., Bitting KJ; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States., Cruse G; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States.; Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Jan 31; Vol. 14, pp. 1006741. Date of Electronic Publication: 2023 Jan 31 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1006741
Abstrakt:	Introduction: Anaphylaxis represents the most extreme and life-threatening form of allergic disease and is considered a medical emergency requiring immediate intervention. Additionally, some people with mastocytosis experience recurrent episodes of anaphylaxis during normal daily activities without exposure to known triggers. While acute therapy consists primarily of epinephrine and supportive care, chronic therapy relies mostly on desensitization and immunotherapy against the offending allergen, which is a time-consuming and sometimes unsuccessful process. These treatments also necessitate identification of the triggering allergen which is not always possible, and thus highlighting a need for alternative treatments for mast cell-mediated diseases. Methods: The exon-skipping oligonucleotide KitStop was administered to mice intradermally, intraperitoneally, or systemically at a dose of 12.5 mg/kg. Local mast cell numbers were enumerated via peritoneal lavage or skin histology, and passive systemic anaphylaxis was induced to evaluate KitStop's global systemic effect. A complete blood count and biochemistry panel were performed to assess the risk of acute toxicity following KitStop administration. Results: Here, we report the use of an exon-skipping oligonucleotide, which we have previously termed KitStop, to safely reduce the severity and duration of the anaphylactic response 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 lead to systemic mastocytosis. Following either local or systemic KitStop treatment, mice had significantly reduced mast cell numbers in the skin and peritoneum. In addition, KitStop-treated mice experienced a significantly diminished anaphylactic response using a model of passive systemic anaphylaxis when compared with control mice. Discussion: KitStop treatment results in a significant reduction in systemic mast cell responses, thus offering the potential to serve as a powerful additional treatment modality for patients that suffer from anaphylaxis. Competing Interests: GC has filed a patent application related to the research reported in this study. An exclusive licensing agreement has been granted to Hoth Therapeutics for this technology. GC has research support from Hoth Therapeutics for a project related to the research reported in this publication and also serves on their Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by NC State University in accordance with its policy on objectivity in research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. (Copyright © 2023 Hedgespeth, Snider, Bitting and Cruse.)
Databáze:	MEDLINE
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