Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin

Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimick the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination.Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.Psoriasis is a chronic inflammatory skin disorder generally manifesting itself as symmetrical, erythematous, and scaling papules and plaques. The disease affects approximately 2-3% of the population worldwide and has a negative impact on the physical wellbeing and the quality of life [1-5]. Histologically, psoriasis displays epidermal hyperplasia, parakeratosis, thinning of stratum granulosum, and dilated and prominent vascularization of the dermis associated with an increased cellular infiltrate of immune cells. The exact cause of psoriasis is unknown, but it is widely accep