Bojanowski Krzysztof, Ibeji Collins U, Singh Parvesh, Swindell William R, Chaudhuri Ratan K
Sunny BioDiscovery, Inc, Santa Paula, California, USA.
Symbionyx Pharmaceuticals Inc, Boonton, New Jersey, USA.
JID Innov. 2021 Jul 8;1(4):100040. doi: 10.1016/j.xjidi.2021.100040. eCollection 2021 Dec.
Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. However, its potential has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide DMF (IDMF), which was designed to have antipsoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is nonirritating and nonsensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically upregulated in psoriatic skin lesions but not those of other skin diseases. IDMF also downregulated genes induced by IL-17A and TNF in keratinocytes as well as predicted targets of NF-κB and the antidifferentiation noncoding RNA (i.e., ). IDMF further stimulated the transcription of oxidative stress response genes (, , ) with stronger NRF2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing the expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data show that IDMF exhibits antipsoriatic activity that is similar or improved compared with that exhibited by DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
富马酸二甲酯（DMF）是一种有效的银屑病口服治疗药物，在欧洲已使用近60年。然而，其应用潜力受到接触性皮炎的限制，这使得它无法进行局部应用。本文对一种DMF衍生物异山梨醇DMF（IDMF）进行了表征，该衍生物旨在具有抗银屑病作用且无皮肤致敏特性。我们发现，IDMF在皮肤成纤维细胞中既不表现出遗传毒性也不具有辐射敏感性，并且在动物模型（大鼠、兔子、豚鼠）中无刺激性和致敏性。对细胞因子刺激的角质形成细胞进行微阵列分析表明，IDMF可抑制银屑病皮肤病变中特异性上调的基因的表达，但不影响其他皮肤疾病相关基因的表达。IDMF还下调了角质形成细胞中由IL-17A和TNF诱导的基因以及NF-κB和抗分化非编码RNA的预测靶点（即 ）。与DMF相比，IDMF进一步刺激了氧化应激反应基因（ 、 、 ）的转录，且NRF2/ARE激活更强。最后，在小鼠中，通过局部应用咪喹莫特引发的银屑病样病变中，IDMF减轻了红斑和鳞屑，同时抑制了免疫反应基因的表达。这些数据表明，IDMF表现出与DMF相似或更好的抗银屑病活性，且没有阻止母体分子局部给药的严重皮肤致敏作用。
