Targeting GATA3 Transcription Factor to Reduce Allergen-Induced Asthmatic Response

Mohammed Naveed Aijaz, Mercer University College of Pharmacy 2016

Asthma is a prevalent disease caused by inflammation of the airway and bronchial smooth muscle constriction. Often associated with both genetics and environmental factors, its especially common in children. 1 Although there is no cure, numerous medications are available for treatment of chronic asthma symptoms as well as acute asthma attacks. These treatments include ß2-adrenergic agonists, such as short acting beta agonists (SABAs), and long acting beta agonists (LABAs). Further studies of patients with allergen-induced asthma have led to the discovery of the type 2 helper T cell (Th2), which has been connected with allergic response in nearly half of asthma patients.2 This endotype of the T cell, which produces various cytokines, is further controlled by the transcription factor GATA3, which is a transcription factor needed for Th2 activation.3 Overexpression of GATA3 has been discovered in patients suffering from severe asthma.4 Thus, it is suspected that this transcription factor may be targeted to prevent its downstream effects and help treat allergen-induced asthma.5

Table 1

Title: Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme6
Design Randomized, double-blind, placebo-controlled; N = 43
Objective To assess efficacy of SB010 vs placebo in controlling symptoms of asthma
Study Groups Two groups:

·      Receiving inhaled SB010 (22 subjects)

·      Receiving placebo (21 subjects)

Methods Subjects were randomized to SB010 treatment or placebo for four weeks. Subjects were given 10 mg of SB010 in 2 ml of phosphate-buffered saline or comparable placebo once daily every morning for 28 days consecutively via nebulizer. Study staff administered treatment on days 1, 7, 13, 20, 26, and 28. On all other days, patients were to self-administer treatment or placebo.
Duration 12 weeks
Primary Outcome Measure Area under the curve (AUC) for forced expiratory volume in one second (FEV1) expressed as a percentage of baseline FEV1 during late asthmatic response (4-7 hours after exposure to allergen), after administration of inhaled SB010
Baseline Characteristics All subjects were white males aged 18-64 years with diagnosis of mild asthma, as classified by guidelines from Global Initiative for Asthma whose disease was of allergic nature.
Results In the SB010 group, 21 patients completed the assessment; in the placebo group 18 patients completed the assessment. The percentage improvement in the mean AUC after treatment as compared to before was 33.7% in the SB010 group reflecting an attenuated asthmatic response when treated with SB0101 compared to a worsened response by 1.4% of the placebo group (P = 0.02).
Adverse Events Common Adverse Events: Asthma symptoms, headache, herpes simplex, nasopharyngitis, diarrhea, nausea; 30% of patients of SB010 group and 23 % patients of placebo group experienced adverse events
Serious Adverse Events: No serious adverse events reported
Percentage that Discontinued due to Adverse Events: None
Study Author Conclusions This proof-of-concept trial showed that treatment with the inhaled DNAzyme in SB010 significantly attenuated both the early-phase and late-phase asthmatic responses after allergen provocation.

 

This study showed that the agent SB010 might be an effective option for controlling allergen-induced asthma response for a subgroup of patients whose disease state and T cell endotypes are similar to those analyzed in this study. This study was statistically significant, however it is not possible to tell yet if this will result in clinical significance since this early trial was done on a very small and limited sample population.

References:

1) Global Initiative for Asthma. Global strategy for asthma management and prevention, 2014. August 12, 2014 (http://www.ginasthma.org/local/uploads/files/GINA_Report_2014_Aug12.pdf).

2) Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716-725Í

3) Bergqvist A, Andersson CK, Hoffmann HJ, et al. Marked epithelial cell pathology and leukocyte paucity in persistently symptomatic severe asthma. Am J Respir Crit Care Med 2013;188:1475-1477

4) Ray A, Cohn L. Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest 1999;104:985-993

5) Holgate ST. Trials and tribulations in identifying new biologic treatments for asthma. Trends Immunol 2012;33:238-246

6) Krug N, Hohlfeld JM, Kirsten AM, et al. Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme. N Engl J Med. 2015; DOI: 10.1056/NEJMoa1411776

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