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The International Pachyonychia Congenita Consortium (IPCC) was founded in 2004 in Park City, Utah, USA. Its goal is to find a cure for pachyonychia congenita, a rare keratinizing disorder. From February 14th–17th, 2013, the group convened in Park City for their tenth annual meeting. The 2013 meeting focused on how to best move forward with clinical trials and on learning from work in other scientific areas, with an emphasis on understanding mechanisms of pain and hyperkeratosis. Considerable time was spent on discussing the best way to move forward with development of new treatments and how to obtain or develop tools that can measure treatment outcomes in PC.

Therapeutics based on short interfering RNAs (siRNAs), which act by inhibiting the expression of target transcripts, represent a novel class of potent and highly specific next-generation treatments for human skin diseases. Unfortunately, the intrinsic barrier properties of the skin combined with the large size and negative charge of siRNAs make epidermal delivery of these macromolecules quite challenging. To help evaluate the in vivo activity of these therapeutics and refine delivery strategies we generated an innovative reporter mouse model that predominantly expresses firefly luciferase (luc2p) in the paw epidermis — the region of murine epidermis that most closely models the tissue architecture of human skin. Combining this animal model with state-of-the-art live animal imaging techniques, we have developed a real-time in vivo analysis work-flow that has allowed us to compare and contrast the efficacies of a wide range nucleic acid-based gene silencing reagents in the skin of live animals. While inhibition was achieved with all of the reagents tested, only the commercially available “self-delivery” modified Accell-siRNAs (Dharmacon) produced potent and sustained in vivo gene silencing. Together, these findings highlight just how informative reliable reporter mouse models can be when assessing novel therapeutics in vivo. Using this work-flow, we developed a novel clinically-relevant topical formulation that facilitates non-invasive epidermal delivery of unmodified and “self-delivery” siRNAs. Remarkably, a sustained > 40% luc2p inhibition was observed after two 1-hour treatments with Accell-siRNAs in our topical formulation. Importantly, our ability to successfully deliver siRNA molecules topically brings these novel RNAi-based therapeutics one-step closer to clinical use., Graphical abstract Unique epidermal mice were combined with IVIS live animal imaging to define nucleic acid-based therapeutic afficacies in vivo and develop a novel clinic-ready siRNA topical delivery formulation.