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Research ArticleDrug Discovery and Translational Medicine

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

Sylvie Colin, Bernadette Darné, Amin Kadi, Antoine Ferry, Maryline Favier, Corinne Lesaffre, Jean-Pascal Conduzorgues, Salman Al-Mahmood and Nejib Doss
Journal of Pharmacology and Experimental Therapeutics April 2014, 349 (1) 107-117; DOI: https://doi.org/10.1124/jpet.113.209346
Sylvie Colin
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.)
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Bernadette Darné
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.)
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Amin Kadi
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.)
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Antoine Ferry
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.)
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Maryline Favier
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.)
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Corinne Lesaffre
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.)
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Jean-Pascal Conduzorgues
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.)
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Salman Al-Mahmood
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.)
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Nejib Doss
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.)
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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.

Footnotes

    • Received September 5, 2013.
    • Accepted February 6, 2014.
  • S.C., B.D., S.A.-M., and N.D. contributed equally to this work.

  • This study was supported by Gene Signal SAS.

  • J.-P.C. is a consultant in product formulation for Gene Signal. S.C. and S.A.-M. are cofounders of Gene Signal, have stock ownership, and are employees of Gene Signal. A.F. possesses stock ownership of Gene Signal. B.D., A.K., M.F., C.L., and N.D. declare no conflicts of interest.

  • dx.doi.org/10.1124/jpet.113.209346.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 1
1 Apr 2014
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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
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Research ArticleDrug Discovery and Translational Medicine

Aganirsen Improves Clinical Signs of Psoriasis

Sylvie Colin, Bernadette Darné, Amin Kadi, Antoine Ferry, Maryline Favier, Corinne Lesaffre, Jean-Pascal Conduzorgues, Salman Al-Mahmood and Nejib Doss
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 107-117; DOI: https://doi.org/10.1124/jpet.113.209346

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Research ArticleDrug Discovery and Translational Medicine

Aganirsen Improves Clinical Signs of Psoriasis

Sylvie Colin, Bernadette Darné, Amin Kadi, Antoine Ferry, Maryline Favier, Corinne Lesaffre, Jean-Pascal Conduzorgues, Salman Al-Mahmood and Nejib Doss
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 107-117; DOI: https://doi.org/10.1124/jpet.113.209346
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