GSNOR Phenotyping/GSNO Challenge in Severe Asthma

Description

S-nitrosylation signaling is relevant to a broad range of diseases, including severe asthma. Work in the Severe Asthma Research Program (SARP) and other research networks has established that asthma is remarkably heterogeneous. The response to standard asthmatic therapies is sub-optimal in many patients. Targeting expected responders, or personalizing approach to treatment, would lead to improved outcomes and decreased treatment costs. Furthermore, since patients with asthma that is not responsive to standard therapies are highly symptomatic despite standard therapy, this subset may derive particular benefit from a personalized approach that includes clinical phenotyping, directed diagnostic testing to confirm underlying pathophysiology, and treatment directed specifically towards those findings.

The classical conceptualization of asthma as a disease of allergic inflammation is based on findings that many patients with asthma have a "Th2 high" phenotype characterized by high circulating levels of IgE, eosinophils and periostin. Patients with these features are particularly amenable to exciting, new antibody-based therapies. However, many patients are not in this phenotype, and, within the generalized phenotype, there is a Gaussian distribution of response. Further, these antibody treatments tend to be expensive and require parenteral administration. A myriad of alternative potential targets has been identified in patients with asthma who do not respond to standard asthma therapies, ranging from high levels of airway chitinase to low levels of vitamin D.

Early work documenting the presence of S-nitrosothiols (SNOs) in human airways and characterizing the potent bronchodilator activity of S-nitrosoglutathione (GSNO) led us to consider that in some patients asthma may represent a disorder in pulmonary SNO homeostasis. The focus of this study is on the subset of patients with asthma who have increased airway S-nitrosoglutathione reductase (GSNOR) activity. Increased activity of GSNOR results in a reduction in the available GSNO, resulting in increased smooth muscle constriction, and increased inflammation. This is a highly targetable process for which specific therapeutic agents are now becoming available. This approach can provide a paradigm for other personalized strategies. Identifying alternative approaches for patients with asthma do not respond to standard asthma therapies has important public health implications. The investigators conservatively estimate that formulation of personalized asthma therapies, including the current study, could halve the morbidity and societal costs of asthma. This in turn would result in fewer disease-related deaths and billions of dollars in economic savings per year in the US - the current annual costs of asthma to the American economy are estimated at $56 billion.

Preliminary work from the Severe Asthma Research Program suggests that patients with increased GSNOR activity and increased catabolism of the endogenous bronchodilator GSNO17 have characteristic phenotypic features (younger age, earlier onset of asthma, higher IgE), but this work needs to be expanded through a combination of mechanistic assessments and clinical testing. The investigators have shown in preliminary work that GSNOR activity in bronchoalveolar lavage (BAL) fluid and in cell lysates from BAL fluid is higher on average in subjects with asthma compared with healthy volunteers. The investigators have further shown the relevance of this finding to asthma in that there is a relationship between GSNOR activity and airway hyper-responsiveness, a hallmark of asthma. The significant linear association between GSNOR activity and the concentration of methacholine that provokes a 20% fall in FEV1 (Forced Expiratory Volume in 1 Second) in subjects with asthma but not in healthy volunteers. While the investigators have shown that GSNOR activity is higher on average in subjects with asthma compared with healthy volunteers, activity levels are quite variable across the spectrum of asthma severity. Accurately identifying patients with asthma who have elevated GSNOR activity levels for targeted therapies is an essential next step.

In the preliminary data, GSNOR activity was measured directly using bronchoscopic techniques to collect BAL fluid and directly measure activity levels. While our experience in the Severe Asthma Research Program shows that bronchoscopies can be done safely in subjects with asthma, it will be important to develop non-invasive methodology to identify patients with asthma and elevated GSNOR activity in order to make if more practical and feasible to test and use targeted treatments. The purpose of this protocol is to confirm previous work demonstrating that subjects with asthma have higher GSNOR activity levels than healthy volunteers, expand our ability to predict who will have elevated GSNOR activity levels based on clinical phenotype, and to develop non-invasive and point of care testing that can accurately identify those with elevated GSNOR levels.

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