Towards the development of a RNAi‐based topical treatment for psoriasis: Proof‐of‐concept in a 3D psoriasis skin model

Abstract

RNA interference has emerged as a powerful tool for therapeutic gene silencing, as it offers the possibility to silence virtually any known pathology-causing gene. However, in vivo delivery of RNAi molecules is hampered by their unfavourable physicochemical characteristics and susceptibility to degradation by endogenous enzymes. To overcome these limitations, we recently developed an elastic liposomal formulation, called DDC642, as topical delivery system of therapeutic RNAi molecules for skin disorders. In this study, we validated the therapeutic efficacy of DDC642-encapsulated RNAi molecules in the treatment of psoriasis using 3 different in vitro models: a standardized keratinocyte monolayer culture, psoriasis-induced keratinocytes and a psoriasis-reconstructed skin model. Four genes (IL22RA1, KRT17, DEFB4 and TSLP), known to be upregulated in psoriatic lesions, and thereby key players in psoriasis pathogenesis were selected. Moreover, the possibility of using a combined siRNA therapy in the topical treatment of psoriasis was explored. Results indicate a successful gene silencing of each different target, both at mRNA and protein levels. Additionally, siRNA-DDC642 treatment resulted in a reduced expression of specific psoriasis markers, indicating their potential in future therapeutic approach. The examined siRNA combination (ie simultaneous knockdown of KRT17, DEFB4 and TSLP) showed an enhanced reduction in TSLP expression, whereas the decrease in K17 protein expression was impaired in psoriatic keratinocytes. Although the here examined siRNA combination could still be further improved, our study proved already in vitro the clinical potential of targeting multiple genes at once, each playing a different role in a complex disease such as psoriasis.

The 3R approach to experimental dermatology

“…Original studies employing alternative methods have been frequently published in Experimental Dermatology in the last years . In line with this tradition, the present special issue also showcases a number of original contributions, which can be viewed as current examples for new developments in alternative methods. The advances in reproducing human skin features in vitro make it possible to recapitulate also human skin diseases, thus replacing the use of animals and/or reducing their number by integrating in vivo and in vitro data.…”

Schwann cells as underestimated, major players in human skin physiology and pathology

“…Experiments targeting the activation of repair SCs and probing SC signalling pathways could be accomplished with ex vivo and in vitro human skin models that are cultured with human neurons differentiated from induced pluripotent stem cells. [ ] The Crispr/Cas9 system could also be used to selective target SC genes in these in vitro and ex vivo models. This question can also be tested in appropriate mouse models.…”

Skin microbiota and human 3D skin models

“…The option to generate 3D skin models with cells derived from patients as well as the possibility to use cells with silenced or enhanced expression of distinct genes of interest could offer valuable approaches to gain more individualised disease‐oriented insight into the impact of the microbiota on human skin biology. In this regard, the use of 3D skin models to assess the impact of RNAi‐based topical treatment options has already been successfully demonstrated …”

“…In this regard, the use of 3D skin models to assess the impact of RNAi-based topical treatment options has already been successfully demonstrated. [60] It is obvious that most published research that has used 3D models to investigate host-microbiota interactions have focused on the impact of individual microbiota species. Thus, there is a clear need to develop and improve experimental strategies for the colonisation of 3D skin models with complete microbiota communities, including those directly isolated from individual humans in order to more closely mimic the in vivo skin-microbiota interplay.…”