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Keywords:

  • allergen challenge;
  • antisense oligonucleotides;
  • asthma;
  • beta subunit of IL-3, IL-5, and GM-CSF receptors;
  • CCR3 receptor

To cite this article: Gauvreau GM, Pageau R, Séguin R, Carballo D, Gauthier J, D’Anjou H, Campbell H, Watson R, Mistry M, Parry-Billings M, Killian K, Renzi PM. Dose–response effects of TPI ASM8 in asthmatics after allergen. Allergy 2011; 66: 1242–1248.

Abstract

Background:  TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (βc) 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™ 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.