Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells.

A major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder.

In order to tackle this problem, we first reviewed different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. The goal of this was to guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing - including gene therapy via siRNA molecules - and to examine biological features contributing to the pathology of psoriasis.

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.

With this in mind, we went on to develop an elastic liposomal formulation, called DDC642, as topical delivery system of therapeutic RNAi molecules for skin disorders. We then 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.

In doing so, 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.