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.