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.).
J Pharmacol Exp Ther. 2014 Apr;349(1):107-17. doi: 10.1124/jpet.113.209346. Epub 2014 Feb 6.
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.
炎症和异常血管生成是导致银屑病的基础。在这里，我们报告称，用 aganirsen 抑制胰岛素受体底物-1（IRS-1）的表达会导致细胞质中 IRS-1 蛋白的剂量依赖性减少（P<0.0001），而 IRS-1 蛋白在核周环境中的数量保持不变。Aganirsen 诱导核周-核可溶性部分中丝氨酸磷酸化 IRS-1 的剂量依赖性增加，诱导 IRS-1-14-3-3β 蛋白的结合（P<0.001），从而破坏 14-3-3β-tristetraprolin 蛋白复合物和富含 AU 的 mRNA 的稳定性（P<0.001）。因此，aganirsen 抑制（P<0.001）体外白细胞介素-8（IL-8）、IL-12、IL-22 和肿瘤坏死因子-α（TNFα）的表达，这四种炎症介质均含有富含 AU 的区域的 mRNA。为了证明这条通路的临床相关性，我们在 12 例银屑病人类患者中进行了一项先导性、双盲、随机、剂量范围研究，通过局部应用 aganirsen 来测试其疗效。经过 6 周的治疗，与安慰剂相比，0.86 和 1.72 mg/g 剂量组的最小平方均数差异分别为-38.9%（95%置信区间，-75.8 至-2.0%）和-37.4%（-74.3 至-0.5%）。病变面积的减小与 IRS-1（P<0.01）、TNFα（P<0.0001）和血管内皮生长因子（P<0.01）表达减少、角质形成细胞增殖减少（P<0.01）以及银屑病皮损中浸润性 CD4+和 CD3+淋巴细胞的正常水平恢复（P<0.02）有关。这些结果表明，aganirsen 是一类新型抗血管生成药物的首创药物，具有抗炎活性。Aganirsen 诱导的富含 AU 的 mRNA 特征性的炎症介质下调可能是其在银屑病中产生有益临床效果的基础。这些结果证明了在银屑病中进一步进行大规模临床试验来确定 aganirsen 的剂量及其长期疗效的合理性。
