Background: Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The\r\npathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine\r\nproduction. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha\r\n(TNFa), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical\r\nuse. We have previously documented the therapeutic applicability of targeting TNFa mRNA for RNA interferencemediated\r\ndown-regulation by anti-TNFa small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted\r\npsoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and\r\nIL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs.\r\nMethods: Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in\r\ncultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated\r\nby bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing\r\nlentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated\r\nby clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.\r\nResults: Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in\r\nxenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are\r\nachieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs.\r\nThese findings mimick the results obtained with anti-TNFa shRNAs but, in contrast to anti-TNFa treatment, anti-\r\nIL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by\r\nimmunohistological examination.\r\nConclusions: Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for\r\nevaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFa treatment, the\r\ntherapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.
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