[HTML][HTML] Amelioration of psoriasis by anti-TNF-α RNAi in the xenograft transplantation model

M Jakobsen, K Stenderup, C Rosada, B Moldt… - Molecular Therapy, 2009 - cell.com
M Jakobsen, K Stenderup, C Rosada, B Moldt, S Kamp, TN Dam, TG Jensen, JG Mikkelsen
Molecular Therapy, 2009cell.com
Tumor necrosis factor-α (TNF-α) is upregulated in psoriatic skin and represents a prominent
target in psoriasis treatment. The level of TNF-α-encoding mRNA, however, is not increased
in psoriatic skin, and it remains unclear whether intervention strategies based on RNA
interference (RNAi) are therapeutically relevant. To test this hypothesis the present study
describes first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs)
targeting human TNF-α mRNA and, next, the transfer of the most potent TNF-α shRNA …
Tumor necrosis factor-α (TNF-α) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-α-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference (RNAi) are therapeutically relevant. To test this hypothesis the present study describes first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs) targeting human TNF-α mRNA and, next, the transfer of the most potent TNF-α shRNA variant, as assessed in vitro, to human skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-α shRNA treatment leads to amelioration of the psoriasis phentotype in the model, as documented by reduced epidermal thickness, normalization of the skin morphology, and reduced levels of TNF-α mRNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-α shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-α shRNAs in human skin. These findings validate TNF-α mRNA as a target molecule for a potential persistent RNA-based treatment of psoriasis and establish the use of small RNA effectors as a novel platform for target validation in psoriasis and other skin disorders.
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