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

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 β protein association ( P β –tristetraprolin protein complex and AU-rich mRNA’s stability ( P P α ), 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 α ( P P P P + 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.