The Notch Pathway Inhibitor SAHM1 Abrogates the Hallmarks of Allergic Asthma

Publication date: Available online 27 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Alex KleinJan, Irma Tindemans, Jeffrey E. Montgomery, Melanie Lukkes, Marjolein J.W. de Bruijn, Menno van Nimwegen, Ingrid Bergen, Raymond E. Moellering, Henk C. Hoogsteden, Louis Boon, Derk Amsen, R.W. Hendriks
BackgroundThe Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by the cell-permeable, hydrocarbon-stapled synthetic peptide SAHM1 was results in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, efficacy of SAHM1 in allergic asthma models has remained unexplored.ObjectiveWe aimed to investigate therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model.MethodsTopical therapeutic intervention with SAHM1 or a control peptide was performed during sensitization and/or challenge with HDM in mice. Airway inflammation was assessed by multi-color flow cytometry and bronchial hyperreactivity (BHR) was studied. Additionally, SAHM1 therapy was investigated in established asthma and in a model in which we neutralized IFNγ during HDM challenge to support the Th2 response and exacerbate asthma.ResultsSAHM1 treatment during the challenge phase led to a marked reduction of eosinophils and T-cells in bronchoalveolar lavage (BAL), compared with diluent-treated or control peptide-treated mice. Likewise, T-cell cytokine content and BHR were reduced. SAHM1 treatment dampened Th2-inflammation during ongoing HDM challenge and enhanced recovery following established asthma. Additionally, in the presence of anti-IFNγ antibodies, SAHM1 downregulated expression of the key Th2 transcription factor (TF) GATA3 and intracellular IL-4 in BAL T-cells, but expression of the Th17 TF RORγt or intracellular IL-17 was not affected. SAHM1 therapy also reduced serum IgE levels.ConclusionsTherapeutic intervention of Notch signaling by SAHM1 inhibits allergic airway inflammation in mice and is therefore an interesting new topical treatment opportunity in asthma.



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