Abstract
Increased inflammation and aberrant angiogenesis underlie psoriasis. Here, we report that the inhibition of insulin receptor substrate-1 (IRS-1) expression with aganirsen resulted in a dose-dependent reduction (P < 0.0001) in IRS-1 protein in the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment. Aganirsen induced a dose-dependent increase in serine-phosphorylated IRS-1 in the soluble perinuclear-nuclear fraction, inducing IRS-1–14-3-3β protein association (P < 0.001), thereby impairing 14-3-3β–tristetraprolin protein complex and AU-rich mRNA’s stability (P < 0.001). Accordingly, aganirsen inhibited (P < 0.001) in vitro the expression of interleukin-8 (IL-8), IL-12, IL-22, and tumor necrosis factor alpha (TNFα), four inflammatory mediators containing mRNA with AU-rich regions. To demonstrate the clinical relevance of this pathway, we tested the efficacy of aganirsen by topical application in a pilot, double-blind, randomized, dose-ranging study in 12 psoriatic human patients. After 6 weeks of treatment, least square mean differences with placebo were −38.9% (95% confidence interval, −75.8 to −2.0%) and −37.4% (−74.3 to −0.5%) at the doses of 0.86 and 1.72 mg/g, respectively. Lesion size reduction was associated with reduced expression of IRS-1 (P < 0.01), TNFα (P < 0.0001), and vascular endothelial growth factor (P < 0.01); reduced keratinocyte proliferation (P < 0.01); and the restoration (P < 0.02) of normal levels of infiltrating CD4+ and CD3+ lymphocytes in psoriatic skin lesions. These results suggest that aganirsen is a first-in-class of a new generation of antiangiogenic medicines combining anti-inflammatory activities. Aganirsen-induced downregulation of inflammatory mediators characterized by AU-rich mRNA likely underlies its beneficial clinical outcome in psoriasis. These results justify further large-scale clinical studies to establish the dose of aganirsen and its long-term efficacy in psoriasis.
Footnotes
- Received September 5, 2013.
- Accepted February 6, 2014.
S.C., B.D., S.A.-M., and N.D. contributed equally to this work.
This study was supported by Gene Signal SAS.
J.-P.C. is a consultant in product formulation for Gene Signal. S.C. and S.A.-M. are cofounders of Gene Signal, have stock ownership, and are employees of Gene Signal. A.F. possesses stock ownership of Gene Signal. B.D., A.K., M.F., C.L., and N.D. declare no conflicts of interest.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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