Umbed Pharmaceuticals, Frederiksberg, Denmark.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Exp Dermatol. 2019 Mar;28(3):261-269. doi: 10.1111/exd.13881. Epub 2019 Feb 12.
Rosacea is a prevalent skin condition dependent on the individual genetic profile. The current pharmacological management of this condition is mostly based on small molecule drugs predominately effective in ameliorating the inflammatory condition. Emerging molecular approaches could present an opportunity for managing rosacea conditions at transcriptomic level, and in the future allow personalized approaches. RNA medicines, such as small RNA interference (siRNA), could provide a flexible and applicable tool reaching this aim. However, the topical siRNA delivery by dermatological emulsions, commonly used in the daily management of rosacea, is still largely unexplored. Consequently, RNA interference application to rosacea was defined on molecular bases by genetic expression meta-data analysis. Based on this, a siRNA directed against TLR2 was designed and validated in vitro on murine macrophages and fibroblasts. Next, siRNA was dispersed in the continuous phase of emulsions and was characterized for commonly used dermatologic bases. Finally, the potential delivery performance of the topical emulsions was tested in vivo on healthy Balb/c mice. It was found that the interaction of siRNA with combination of excipients, such as urea and glycerol, is likely to favour the siRNA delivery, inducing genetic silencing of TLR2. These findings provide a foundation for the future development of topical RNA-based dispersions for topical molecular medicines, by emphasizing on the formulation and therapeutic-based opportunities with dermatological treatments.
酒渣鼻是一种依赖个体遗传特征的常见皮肤疾病。目前，这种疾病的药物治疗主要基于小分子药物，这些药物主要能改善炎症状况。新兴的分子方法可能为转录组水平上的酒渣鼻疾病管理提供机会，并在未来允许采用个性化方法。RNA 药物，如小干扰 RNA（siRNA），可以提供一种灵活且适用的工具来实现这一目标。然而，通过皮肤科乳剂进行局部 siRNA 传递，这在酒渣鼻的日常管理中经常使用，但仍在很大程度上未被探索。因此，基于遗传表达元数据分析，明确了 RNA 干扰在酒渣鼻中的应用。在此基础上，设计并验证了一种针对 TLR2 的 siRNA 在体外的鼠巨噬细胞和成纤维细胞中的效果。接下来，将 siRNA 分散在乳剂的连续相中，并对常用的皮肤科基础进行了表征。最后，在健康的 Balb/c 小鼠体内进行了局部乳剂的潜在传递性能测试。研究发现，siRNA 与赋形剂（如尿素和甘油）的相互作用可能有利于 siRNA 的传递，从而诱导 TLR2 的基因沉默。这些发现为未来开发用于局部分子药物的局部 RNA 分散体提供了基础，强调了制剂和治疗方面与皮肤科治疗相关的机会。
