Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

作者：Krug, Norbert; Hohlfeld, Jens M.; Kirsten, Anne-Marie; Kornmann, Oliver; Beeh, Kai M.; Kappeler, Dominik; Korn, Stephanie; Ignatenko, Stanislav; Timmer, Wolfgang; Rogon, Cordelia; Zeitvogel, Jana; Zhang, Nan; Bille, Joachim; Homburg, Ursula; Turowska, Agnieszka; Bachert, Claus; Werfel, Thomas; Buhl, Roland; Renz, Jonas; Garn, Holger; Renz, Harald^*

来源：New England Journal of Medicine, 2015, 372(21): 1987-1995.

DOI：10.1056/NEJMoa1411776

• INDUCED AIRWAY INFLAMMATION
• EOSINOPHILIC ASTHMA
• INHALED ALLERGEN
• INHALATION
• PHENOTYPES
• CELL
• MEPOLIZUMAB
• CHALLENGE
• INNATE
• RESPONSIVENESS

BACKGROUND @@@ The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). @@@ METHODS @@@ We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1). @@@ RESULTS @@@ After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P = 0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P = 0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. @@@ CONCLUSIONS @@@ Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses.

• 出版日期2015-5-21