The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3ß-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 < 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-1-14-3-3ß protein association (P < 0.001), thereby impairing 14-3-3ß-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.

[Good and bad fortunes of drugs]. / Heurs et malheurs d'un médicament.

A drug's lifetime, whether it is short or long, may go through fantastic new developments. Such is the case with beta-blockers, some of which have long been prescribed in heart failure before having made the definite proof of their efficacy, provided they are used carefully regarding the Good Product Use. On the other hand, the development of mibefradil, a calcic antagonist prescribed in the treatment of hypertension and angina pectoris, was stopped abruptly a few weeks before its launching because of the occurrence of serious side effects in patients suffering from heart failure. These examples, which are taken amongst others, clearly show the difficulties encountered by pharmaceutical companies that are concerned in putting forward innovative, efficacious, and ... secure drugs.