BACKGROUND: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(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™ 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.
BACKGROUND:TPIASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPIASM8 had broader effects than just inhibition of eosinophils in asthmatics. OBJECTIVE: We assessed whether TPIASM8 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 TPIASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods. RESULTS:TPIASM8 was safe and well tolerated at all doses. TPIASM8 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, TPIASM8 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:TPIASM8 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.
Authors: Timothy R Hercus; Winnie L T Kan; Sophie E Broughton; Denis Tvorogov; Hayley S Ramshaw; Jarrod J Sandow; Tracy L Nero; Urmi Dhagat; Emma J Thompson; Karen S Cheung Tung Shing; Duncan R McKenzie; Nicholas J Wilson; Catherine M Owczarek; Gino Vairo; Andrew D Nash; Vinay Tergaonkar; Timothy Hughes; Paul G Ekert; Michael S Samuel; Claudine S Bonder; Michele A Grimbaldeston; Michael W Parker; Angel F Lopez Journal: Cold Spring Harb Perspect Biol Date: 2018-06-01 Impact factor: 10.005
Authors: Nicola L Diny; Xuezhou Hou; Jobert G Barin; Guobao Chen; Monica V Talor; Julie Schaub; Stuart D Russell; Karin Klingel; Noel R Rose; Daniela Čiháková Journal: Eur J Immunol Date: 2016-10-25 Impact factor: 5.532
Authors: Susanne Radonjic-Hoesli; Peter Valent; Amy D Klion; Michael E Wechsler; Hans-Uwe Simon Journal: Annu Rev Pharmacol Toxicol Date: 2014-10-17 Impact factor: 13.820