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Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model.

ABSTRACT: Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-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-alpha mRNA and, next, the transfer of the most potent TNF-alpha shRNA variant, as assessed in vitro, to human skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-alpha 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-alpha mRNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha 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.

SUBMITTER: Jakobsen M

PROVIDER: S-EPMC2835022 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Genome-wide association analysis of anti-TNF-α treatment response in Chinese patients with psoriasis.

Project description:Background: TNF-α inhibitors are effective biological agents for treating psoriasis, but the treatment responses differ across patients. This study aimed to identify genetic biomarkers of anti-TNF-α response in Chinese psoriasis patients using a genome-wide association approach. Methods: We recruited two independent cohorts of Chinese psoriasis patients administered etanercept biosimilar (with or without methotrexate). We identified 61 and 87 good responders (PASI improvement ≥75%), 19 and 10 poor responders (PASI improvement <50%) after 24 weeks treatment in the two cohorts, respectively. Then we performed genome-wide association studies (GWAS) on anti-TNF-α response in each cohort independently, followed by a fixed-effects inverse-variance meta-analysis in the 148 good and 29 poor responders. Results: We tested genetic associations with >3 million genetic variants in either cohort. Meta-analysis identified significant associations within seven loci at p < 10-5, which also showed consistent association evidence in the two cohorts. These seven loci include rs2431355 (OR = 6.65, p = 4.46 × 10-7, IQGAP2-F2RL2 on 5q13.3), rs11801616 (OR = 0.11, p = 1.75 × 10-6, SDC3 on 1p35.2), rs3754679 (OR = 0.17, p = 7.71 × 10-6, CNOT11 on 2q11.2), rs13166823 (OR = 0.09, p = 3.71 × 10-6, IRF1-AS1 on 5q31.1), rs10220768 (OR = 5.49, p = 1.48 × 10-6, NPAP1 on 15q11.2), rs4796752 (OR = 5.56, p = 1.49 × 10-6, KRT31 on 17q21.2), and rs13045590 (OR = 0.08, p = 9.67 × 10-7, CTSZ on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect (p < 1 × 10-6) for several genes in multiple tissues. Conclusion: These results suggest novel biological mechanisms and potential biomarkers for the response to anti-TNF therapies. These findings warrant further validation.

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Project description:Adalimumab and secukinumab are commonly used for moderate to severe psoriasis vulgaris (PV). Although distinct individual responses to and impaired effectiveness of these biological agents occur occasionally, little is known about the underlying reasons. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using data-independent acquisition mass spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed that DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. The results of parallel reaction monitoring (PRM) analysis suggested that S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There was a positive association between the Psoriasis Area and Severity Index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study findings suggest that inhibition of IL-17A and TNF-α can induce changes in multiple molecules in psoriatic lesions and have an overlapping influence on the immune response and process through direct or indirect effects.

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