Dose-response effects of TPI ASM8 in asthmatics after allergen
Dose-response effects of TPI ASM8 in asthmatics after allergen
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DOI：
10.1111/j.1398-9995.2011.02638.x
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发表时间：
2011-09-01
期刊：
影响因子：
12.4
通讯作者：
Renzi, P. M.
中科院分区：
文献类型：
--
作者：
Gauvreau, G. M.;Pageau, R.;Renzi, P. M.
背景：TPI ASM8 含有两个修饰的反义寡核苷酸 (AON)，靶向 IL-3、IL-5、GM-CSF 受体和趋化因子受体 CCR3 的 β 亚基 (beta(c))。先前的一项研究表明，TPI ASM8 对哮喘患者的作用不仅仅是抑制嗜酸性粒细胞。目的：我们评估了 TPI ASM8 是否会导致吸入过敏原激发 (AIC) 后炎症和生理变化的剂量依赖性减弱。方法：这项单中心、开放标签、逐步递增的剂量研究在 14 名稳定的轻度过敏性哮喘患者中进行。安慰剂 AIC 治疗后，受试者通过 I-Neb (TM) 雾化器吸入 1、2 和 4 mg BID，最后每天一次 (OD) 8 mg TPI ASM8，治疗 4 天后接受 AIC。治疗间隔为 2-3 周的清除期。结果：TPI ASM8 在所有剂量下都是安全的且耐受性良好。 TPI ASM8 8 mg OD 可减少 AIC 后痰液中的嗜酸性粒细胞（AIC 后 7 小时和 24 小时分别减少 60.9% 和 68.4%，P = 0.016 和 P = 0.007）。此外，TPI ASM8 8 mg OD 显着减弱早期和晚期气道反应，曲线下面积分别减少 45% (P = 0.016) 和 59% (P = 0.0015)，嗜酸性粒细胞阳离子蛋白 (ECP) 增加高达 57% (P = 0.021)，气道对乙酰甲胆碱的反应性增加超过1 倍剂量（P = 0.012）。注意到剂量反应关系，并且每天给药一次仍能保持疗效。结论：TPI ASM8 减轻了 AIC 后的广泛炎症和生理变化，表明 CCR3、IL-3 和 GM-CSF 也是哮喘治疗的重要靶标。
Background: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (beta(c)) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics.Objective: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC).Methods: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb (TM) nebuliser. Treatments were separated by 2-3-week washout periods.Results: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P = 0.016 and P = 0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P = 0.016) and 59%, (P = 0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P = 0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P = 0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration.Conclusions: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma.