Self-Delivering RNAi Compounds for Reduction of Hyperpigmentation

Abnormal melanin synthesis causes hyperpigmentation disorders like melasma and lentigines, impacting psychological well-being. RNA interference (RNAi) uses small RNA molecules to inhibit gene expression by targeting specific mRNA, silencing genes involved in undesirable cellular functions. This study assessed INTASYL compounds, self-delivering RNAi molecules, designed to target and reduce tyrosinase gene expression to decrease pigmentation.

36 INTASYL compounds were designed to target and reduce TYR gene expression and tested in a screening assay. RXI-231, the lead compound, was tested in normal human epithelial melanocytes and the MelanoDerm™ model, a 3D reconstituted human epidermal culture. RXI-231 was evaluated for its ability to reduce tyrosinase mRNA expression, in vitro dopachrome formation, and melanin content. Penetration of fluorescently labeled INTASYL compounds through the stratum corneum into the epidermis was tested in cultured porcine skin explants using a DermaPen^® microneedle device and a proprietary mixture of penetration enhancers. RXI-231 was also tested for skin irritation in the MatTek EpiDerm™ model to determine its non-irritant profile.

RXI-231 significantly reduced tyrosinase mRNA expression, dopachrome formation, and melanin content in both normal human melanocytes and the MelanoDerm model. Application of INTASYL compounds every other day visibly reduced pigmentation in the 3D epidermal cultures. Penetration studies showed efficient delivery into the epidermis, overcoming the stratum corneum barrier. RXI-231 showed no irritation, with viability above 50% in the MatTek EpiDerm model, confirming its non-irritant profile.

RXI-231 effectively reduced tyrosinase activity and melanin synthesis, showing promise for treating hyperpigmentation disorders. Further characterization and planned human patient testing are necessary to confirm its clinical potential patient.