Veit J G S, Poumay Y, Mendes D, Kreitinger J, Walker L, Paquet A, Menigot C, Zolezzi F, Paller A S, Diaz P
Department of Biomedical and Pharmaceutical Sciences University of Montana Missoula Montana USA.
URPHYM-NARILIS University of Namur Namur Belgium.
Skin Health Dis. 2021 Mar 26;1(2):e22. doi: 10.1002/ski2.22. eCollection 2021 Jun.
Retinoid-based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non-specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings.
Characterize the therapeutic potential of recently discovered, CYP26-selective RAMBA, DX308.
Preliminary in vitro assessment of potential off-target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways.
In vitro, DX308 does not interact with off-target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid-responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs.
These preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid-responsive skin ailments.
基于维甲酸的疗法常用于治疗角化异常及其他皮肤疾病，但可能会产生非特异性效应和不良反应。使用诸如DX308之类的维甲酸代谢阻断剂（RAMBAs）或许可以解决这些缺点。
表征最近发现的CYP26选择性RAMBA——DX308的治疗潜力。
对潜在的脱靶活性、代谢和毒理学概况进行初步体外评估。开展研究以评估局部治疗在纠正犀牛小鼠异常皮肤形态方面的安全性和有效性。通过RNA测序和qPCR对来自角化异常患者和健康对照者的角质形成细胞（KCs）所培养的3D表皮进行广泛的基因表达谱分析，以研究维甲酸生物途径的调节情况。
在体外，DX308不与脱靶核受体或CYP450相互作用，无基因毒性，且尽管在肝脏中有活跃的代谢，但在皮肤中稳定。在体内，局部应用DX308可诱导粉刺溶解和表皮增厚，且无明显不良反应。基因表达谱分析显示，DX308在健康和角化异常的KCs中均能有效调节维甲酸反应性基因。通路分析表明，DX308可能抑制KCs中的炎症和免疫反应。
这些初步研究表明，DX308是一种有效的局部治疗药物，具有良好的代谢和安全性。DX308可能为治疗角化异常及其他维甲酸反应性皮肤疾病提供一种更好的治疗选择。
