A Novel Glucocorticoid with Limited Adverse Effects in Neonatal Brain

支气管肺发育不良（BPD）仍然是早产儿的一个重要并发症，发病率为7% 在所有早产儿和近70%的新生儿中， ≤28周。目前的临床策略，以减轻 BPD的发生和进展包括机械通气和药物治疗， 表面活性剂和长效合成糖皮质激素（sGC）如地塞米松（Dex）。产后 sGC限制新生儿的炎症并减少BPD进展，它们具有显著的不良反应风险。 对神经发育的影响，导致大脑结构和功能的长期改变。具体地说， 最近的新生儿sGC治疗结果研究表明，脑瘫的风险增加， 注意到剂量和时间的差异。因此，美国科学院目前的临床实践指南 儿科不推荐高剂量Dex;“没有足够的证据提出建议 关于低剂量地塞米松的治疗”。总而言之，仍然需要一个GC 新生儿BPD的药物治疗将具有有益的抗炎和肺成熟 影响，但有限的不良反应，特别是在大脑中。由于啮齿类新生儿易受 与人类出生后sGC的不利神经发育影响类似，它们提供了一个机会， 进行机制研究，并确定更有针对性的新型sGC治疗的靶点和方式。 环索奈德（CIC）是新一代吸入性sGC，目前已被批准用于治疗哮喘和过敏性鼻炎。 鼻炎它是一种前药，通过成人下气道中富集的羧酸酯酶（CES）转化为 活性化合物去异丁酰环索奈德（des-CIC），一种高效的糖皮质激素激动剂 受体的CIC被批准作为5岁及以上儿童的替代疗法，目前正在评估中 在一项治疗2岁儿童过敏性鼻炎的3期临床试验中，我们假设 新生儿暴露于sGC前药CIC不会引发脱髓鞘、星形胶质细胞增生或小脑胶质细胞增生。 Dex引起的新生儿脑损伤，由于对des-CIC的积累和/或反应的限制， CIC的活性代谢产物。该方案中的实验利用了一种新的“人源化”敲除小鼠系 其去除血浆Es-1基因以更接近人体中的CIC代谢， 不像啮齿类动物缺乏血浆CES。具体目标是：1）测量游离脂肪酸的积累- 在雄性和雌性Es-1-/-小鼠的各种新生组织中检测结合的des-CIC，并评估 新生儿脑和肺中的Ces基因表达，以及2）测量脑中对CIC的体内生物学应答 雄性和雌性Es-1-/-新生小鼠的肺。考虑到CIC在非常年轻的 儿童，我们提出的研究人类新生儿的临床转化可以加快， 特别是考虑到目前可用于治疗或预防BPD的有限的安全治疗选择 易受感染的早产儿。

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.