Department of Anatomy and Developmental Biology, Development and Stem Cell Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Melbourne, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.
Cell Rep Med. 2020 Nov 17;1(8):100129. doi: 10.1016/j.xcrm.2020.100129.
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.
ABCA12 脂质转运蛋白突变导致危及生命的皮肤疾病——丑角样鱼鳞病（HI），其特征是皮肤屏障功能丧失、炎症和脱水。HI 中的炎症反应通过损害角质形成细胞分化来加重疾病严重程度，这表明改善这种表型可能是该疾病的一种潜在治疗方法。HI 的现有治疗方法基于使用维甲酸，但相对于其他改善的管理方案，它们在新生儿期治疗患者的价值受到质疑，并且长期使用与副作用相关。我们已经开发了一种条件性小鼠模型，证明氨基水杨酸盐衍生物 5ASA 或 4ASA 的局部应用可显著改善 HI 角质形成细胞分化，而不会产生维甲酸acitretin 和水杨酸（阿司匹林）的不良副作用。基因表达变化的分析表明，4ASA 特别引起与屏障功能相关的一大类基因的代偿性上调，其中许多基因与其他鱼鳞病有关，这表明该化合物是开发 HI 局部治疗的潜在候选药物。
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