Topical Application of Self-delivering RNAi (sd-rxRNA®) Compounds for Reduction of Hyperpigmentation

Melissa Maxwell, Katherine Holton, James Cardia, Richard Looby,Michael Byrne,Karen Bulock RXi Pharmaceuticals

There are a number of dermal hyperpigmentation disorders that have a potentially negative impact on a person’s psychological well-being. These disorders are 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 results 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 designed, synthesized, and screened to identify RXI-231, a lead compound for the potential use to improve the appearance of skin. RXI-231 was further tested in normal human embryonic melanocytes and MelanoDerm, a 3-dimensional 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 of these models. Topical application of RNAi compounds targeting skin pigmentation is desirable but notoriously difficult. Penetration through the stratum corneum is particularly challenging due to the large size and negative charge of the compounds. We have developed a 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. Testing in cultured porcine skin explants shows good penetration of fluorescently labeled sd-rxRNAcompounds through the stratum corneum and into the epidermis. Efforts are underway to characterize the gene silencing in this model. Human subject testing is planned in early 2017.


hyperpigmentation, MelanoDerm, RNA interference (RNAi), tyrosinase, melanin content, skin irritation

Materials Tested

self-delivering RNA (sd-RNA)

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