1257 Topical application of self-delivering RNAi (sd-rxRNA®) compounds for reduction of hyperpigmentation

Abstract

There are many dermal hyperpigmentation disorders caused by an over-production of melanin. The enzyme tyrosinase catalyzes the rate-limiting steps in the production of melanin by melanocytes and inhibition of tyrosinase may result in a reduction in pigmentation. We have developed a new class of stable, self-delivering RNAi compounds that incorporate features of RNAi and antisense technology. sd-rxRNAs demonstrate potent activity, stability, and reduced immune stimulation, and are rapidly and efficiently taken up by cells. Tyrosinase-targeting sd-rxRNAs were screened to identify RXI-231, a lead compound to be developed as a cosmetic ingredient for improvement of skin tone. RXI-231 was tested in normal human embryonic melanocytes and MelanoDerm, a 3D reconstituted human epidermal culture model. Treatment with RXI-231 resulted in a reduction in tyrosinase mRNA expression, in vitro dopachrome formation, and melanin content in both models. We have developed a topical gel formulation that enables non-invasive epidermal delivery of our compounds using a proprietary mixture of penetration enhancers that can be used in cosmetic or pharmaceutical formulations. A consumer testing program consisting of 3 studies was carried out. The first 2 studies were human repeat insult patch tests (hRIPT). Results from a 14-day cumulative irritation assay and human maximization test showed that RXI-231 gel did not cause irritation or sensitization to human skin. A third study investigated the potential of RXI-231 to impact a skin melanin content (pigmentation) increase induced by UV in healthy volunteers, as measured by narrow-band reflectance spectroscopy. The spectroscopic results - known to correlate well with skin melanin content - demonstrated that application with RXI-231 containing gel can reduce a change of skin tone triggered by UV exposure, as compared to vehicle control (p < 0.04). Combined with the preclinical data, these clinical results suggest that RXI-231 may impact skin pigmentation induced by UV exposure.