title: 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.
authors: Gene Signal SAS, Evry, France (S.C., A.F., S.A.-M.); Monitoring Force Group, Maisons-Laffitte, France (B.D., A.K.); Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016, CNRS UMR8104, Morphology and Histology Platform and Université Paris Descartes, Paris, France (M.F., C.L.); AMATSI, St. Gely du Fesc, France (J.-P.C.); and Université de Tunis El Manar, Faculté de Médecine de Tunis, Military Hospital of Tunis, Department of Dermatology, Tunis, Tunisia (N.D.).
authors: Sylvie
authors: S
authors: Colin
authors: Bernadette
authors: B
authors: Darné
authors: Amin
authors: A
authors: Kadi
authors: Antoine
authors: A
authors: Ferry
authors: Maryline
authors: M
authors: Favier
authors: Corinne
authors: C
authors: Lesaffre
authors: Jean-Pascal
authors: JP
authors: Conduzorgues
authors: Salman
authors: S
authors: Al-Mahmood
authors: Nejib
authors: N
authors: Doss
mesh_terms: D063307:AU Rich Elements; D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010865:Pilot Projects; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome; D051816:Tristetraprolin / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; C540750:GS 101; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009841:Oligonucleotides; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human