Increased inflammation and aberrant angiogenesis underlay psoriasis. Here, we report that the inhibition of IRS-1 expression with aganirsen resulted in a dose-dependent reduction (P<0.0001) in IRS-1 protein at the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment. Aganirsen induced a dose-dependent increase in serine-phosphorylated IRS-1 (pIRS-1Ser) in the soluble perinuclear-nuclear fraction (SPN), inducing IRS-1-14-3-3beta protein association (P<0.001), thereby impairing 14-3-3β-tristetraprolin protein (TTP) 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) and tumour necrosis factor alpha (TNFalpha), two 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 means differences with placebo were -38.9% (95%CI [-75.8%; -2.0%]) and -37.4% [-74.3%; -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 VEGF (P<0.01), reduced keratincytes 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 sugges that aganirsen is a first in class of new generation of anti-angiogenic medicines which combine antiangiogenic and anti-inflammatory activities. We suggest that these two properties of aganirsen synergize to provide the beneficial clinical outcome in psoriasis. These results justify further large-scale clinical studies to establish the long-term efficacy of aganirsen in psoriasis.
- The American Society for Pharmacology and Experimental Therapeutics