1. Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis.
- Author
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Cottle DL, Ursino GMA, Jones LK, Tham MS, Zylberberg AK, and Smyth IM
- Subjects
- ATP-Binding Cassette Transporters metabolism, Acitretin pharmacology, Animals, Disease Models, Animal, Epidermis drug effects, Epidermis metabolism, Gene Expression drug effects, Ichthyosis, Lamellar metabolism, Keratinocytes metabolism, Mice, Mice, Knockout, Mutation drug effects, Phenotype, Salicylic Acid pharmacology, Skin drug effects, Skin metabolism, Up-Regulation drug effects, Aminosalicylic Acid pharmacology, Cell Differentiation drug effects, Ichthyosis, Lamellar drug therapy, Keratinocytes drug effects
- Abstract
Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI., Competing Interests: D.L.C., G.M.A.U., and I.M.S. are inventors on patent applications WO 2016/145488 A1, PCT/AU2016/050185, US 15/557405, India 201727036282, Europe 16764064.8, Australia 2016232987, Canada 2984949, Japan 2017-549008, and China 201680028353.X, related to ASA treatment of ichthyosis skin diseases and received funding from Factor Therapeutics under a research collaboration and option agreement., (© 2020 The Authors.)
- Published
- 2020
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