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The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3β-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients.

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.
AuthorsSylvie Colin, Bernadette Darné, Amin Kadi, Antoine Ferry, Maryline Favier, Corinne Lesaffre, Jean-Pascal Conduzorgues, Salman Al-Mahmood, Nejib Doss
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 349 Issue 1 Pg. 107-17 (Apr 2014) ISSN: 1521-0103 [Electronic] United States
PMID24504098 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Cytokines
  • GS 101
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Oligonucleotides
  • RNA, Messenger
  • Tristetraprolin
  • ZFP36 protein, human
Topics
  • AU Rich Elements
  • Administration, Topical
  • Angiogenesis Inhibitors (administration & dosage, adverse effects, therapeutic use)
  • Cytokines (antagonists & inhibitors, immunology)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins (antagonists & inhibitors)
  • Male
  • Microvessels (drug effects, metabolism)
  • Middle Aged
  • Oligonucleotides (administration & dosage, adverse effects, therapeutic use)
  • Pilot Projects
  • Psoriasis (drug therapy, immunology, metabolism, pathology)
  • RNA Stability (drug effects)
  • RNA, Messenger (genetics, physiology)
  • Skin (blood supply, drug effects, immunology, pathology)
  • Treatment Outcome
  • Tristetraprolin (metabolism)

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