A Novel Glucocorticoid with Limited Adverse Effects in Neonatal Brain

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Bronchopulmonary dysplasia (BPD) remains a significant complication of prematurity with an incidence of 7% in all preterm infants and nearly 70% in infants born ≤28 weeks. Current clinical strategies to mitigate the development and progression of BPD include mechanical ventilation and pharmacologic therapy including surfactants and long-acting synthetic glucocorticoids (sGCs) such as dexamethasone (Dex). While postnatal sGCs limit inflammation and reduce BPD progression in neonates, they carry a significant risk of adverse effects on neurodevelopment leading to long-lasting alterations in brain structure and function. Specifically, recent outcome studies of neonatal sGC therapy have demonstrated increased risk for cerebral palsy, with noted dosage and timing differences. As a result, current clinical practice guidelines of the American Academy of Pediatrics do NOT recommend high-dose Dex; “there is insufficient evidence to make a recommendation regarding treatment with low-dose dexamethasone”. In summary, there remains a need for a GC pharmacotherapy for BPD in neonates that will have beneficial anti-inflammatory and lung maturation effects, but limited adverse reactions, particularly in the brain. Since rodent neonates are susceptible to analogous adverse neurodevelopmental effects of postnatal sGCs as humans, they provide an opportunity to perform mechanistic studies and identify targets and modalities for more directed, novel sGC therapeutics. Ciclesonide (CIC) is a new generation inhaled sGC currently approved for the treatment of asthma and allergic rhinitis. It is a prodrug that is converted by carboxylesterases (CESs) enriched in the lower airway of adults into the active compound desisobutyryl-Ciclesonide (des-CIC), a highly potent agonist for the glucocorticoid receptor. CIC is approved as an alternate therapy in children 5 years of age and older and is being evaluated in a Phase 3 clinical trial for treatment of allergic rhinitis in children as young as 2 years old. We hypothesize that neonatal exposure to the sGC prodrug, CIC, will NOT trigger the demyelination, astrogliosis or cerebellar damage in neonatal brain caused by Dex, due to limitations in accumulation of and/or response to des-CIC, the active metabolic product of CIC. Experiments in this proposal utilize a novel “humanized” knockout mouse line that is ablated of the plasma Es-1 gene in order to more closely approximate CIC metabolism in humans, which unlike rodents lack plasma CES. Specific aims will 1) measure the accumulation of free and fatty acid- conjugated des-CIC in various neonatal tissues of male and female Es-1-/- mice and assess the ontogeny of Ces gene expression in neonatal brain and lung, and 2) measure in vivo biological responses to CIC in brain and lung of male and female Es-1-/- neonatal mice. Given the established safety of CIC in very young children, the clinical translation of our proposed studies to human neonates could be expedited, particularly given the limited safe therapeutic options currently available for treating or preventing BPD in susceptible premature infants.