TECHNICAL FIELD

This application relates to compositions and methods of modulating S-nitrosoglutathione (GSNO) in subjects with respiratory disorders associated with hyperoxia and particularly relates to the use of GSNO reductase inhibitors to treat hyperoxia-induced air responsiveness, respiratory distress syndrome, and bronchopulmonary dysplasia.

BACKGROUND

Globally, more than 11% of babies are born before 37 weeks of gestation (premature), and the number of premature births is increasing worldwide (Blencowe et al., (2012)Lancet379:2162-2172). Bronchopulmonary dysplasia (BPD) is the major pulmonary morbidity of extreme prematurity, with an estimated 14,000 new diagnoses made each year in the United States (Van Marter (2009)Semin Fetal Neonatal Med14:358-366) and annual care costs upwards of $26 billion (Cole et al., (2011) Pediatrics 127:363-369). Equally important is the concept that prematurity and BPD may be a chronic respiratory condition. After their initial care, half of premature patients will be rehospitalized for respiratory causes in early childhood (Furman et al., (1996)The Journal of Pediatrics128:447-452). Follow up studies of children and young adults born prematurely show evidence of impaired pulmonary function, manifesting signs of obstructive pulmonary disease with decreased predicted forced expiratory volume in 1 second (FEV1) (Fawke et al. (2010)Am J Respir Crit Care Med182:237-247), decreased predicted forced expiratory flow (FEF25-75%) (Vollsaeter et al. (2013)Thorax68:767-776), and reduced exercise capacity (Vrijlandt et al., (2006)Am J Respir Crit Care Med173:890-896). Indeed, increased airway reactivity and asthma-like symptoms are common long-term pulmonary consequences of both premature birth and BPD (Baraldi et al., (2009)Early Human Development85:S1-3).

S-nitrosothiols (SNOs) are ubiquitous protein molecules in which nitric oxide is bound to a cysteine thiol, which regulate the biologic activity of many target proteins (Foster et al., (2009)Trends in Molecular Medicine15:391-404). One such SNO is S-nitrosoglutathione (GSNO), an endogenous bronchodilator, which exhibits 100-fold more potency than the asthma medication theophylline (Gaston et al., (1994)J Pharmacol Exp Ther268:978-984). GSNO is a critical modulator of airway reactivity in asthmatic animal models (Blonder et al., (2014)BMC Pulm Med14:3). Airway levels of GSNO are dramatically decreased in pediatric cases of severe asthmatic respiratory failure (Gaston et al., (1998)Lancet351:1317-1319) and GSNO reductase (GSNOR, also known as alcohol dehydrogenase 5, adh5), the enzyme responsible for the catabolic breakdown of GSNO, is elevated in asthma patients that display increased airway reactivity (Que et al. (2009)American Journal of Respiratory and Critical Care Medicine180:226-231).

Traditional asthma therapies are not always effective in this patient population. Interestingly, the asthma phenotype in premature infants differs from the allergic asthma seen in their term-born peers (Filippone et al., (2013)Eur Respir J42:1430-1431). The increased risk for airway reactivity in surviving premature neonates is strongly associated with a history of prolonged supplemental oxygen exposure and bronchopulmonary dysplasia (BPD), compared to the reactivity observed in full term peers, which instead is associated with a history of genetic inheritance, allergy, airway inflammation, and cigarette exposures (Halvorsen et al., (2005)Pediatr Allergy Immunol16:487-494). Yet, former premature infants are twice as likely to be prescribed asthma medications compared to their full term school-age classmates (Hack et al., (2005)JAMA294:318-325) and premature infants, with or without BPD, continue to be at very high risk for airway reactivity in infancy and childhood (Fawke et al. (2010)Am J Respir Crit Care Med182:237-247; Been et al., (2014)PLoS Med11:e1001596; Hennessy et al., (2013)J Pediatr163:61-66 e61). Thus, novel therapies are needed in this growing patient population.

SUMMARY

Embodiments described herein relate to the targeted replacement of depleted S-nitrosoglutathione (GSNO) stores in the developing lungs of infant and child subjects born prematurely and potentially treated with prolonged supplemental oxygen by administration of GSNO directly to the subject and/or inhibition of S-nitrosoglutathione reductase (GSNOR) in the subject, and particularly relates to methods of treating and/or preventing hyperoxia induced respiratory disorders, such as respiratory distress syndrome or bronchopulmonary dysplasia (BPD), in premature subjects in need thereof, including those premature subjects receiving life saving newborn interventions, such as supplemental oxygen and mechanical ventilation, by administering to the subjects GSNO and/or a GSNO promoting agent.

In some embodiments GSNO or a GSNO promoting agent can be administered to a subject, such as a premature subject, to raise the subject's GSNO levels and treat disorders associated with GSNO deficiency, such as hyperoxia induced respiratory disorders associated with prolonged supplemental oxygen treatment. The GSNO and/or GSNO promoting agent can be administered to the subject at a therapeutically effective amount(s) in a pharmaceutical composition comprising GSNO and/or a GSNO promoting agent and at least one pharmaceutically acceptable carrier.

Other embodiments described herein relate to methods of treating BPD in a subject in need thereof. Such a method comprises administering a therapeutically effective amount of a pharmaceutical composition including GSNO and/or a GSNO promoting agent and at least one pharmaceutically acceptable carrier.

Still other embodiments described herein relate to methods of treating a BPD, such as hyperoxia induce BPD, in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising a pyrrole inhibitor of GSNOR and at least one pharmaceutically acceptable carrier.

