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，发生率为7%。 在所有早产儿中，近70%在新生儿中 ≤为28周。目前的临床策略是缓解 BPD的发展和进展包括机械通气和药物治疗，包括 表面活性剂和长效合成糖皮质激素(SGC)，如地塞米松(Dex)。而在出生后 SGCs可以抑制新生儿的炎症反应并减缓BPD的进展，它们具有显著的不良风险。 对神经发育的影响导致大脑结构和功能的长期变化。具体来说， 最近对新生儿sGC治疗的结果研究表明，脑瘫的风险增加， 注意到剂量和时间上的差异。因此，美国科学院现行的临床实践指南 儿科医生不推荐大剂量的地塞米松；“没有足够的证据来提出建议 关于小剂量地塞米松的治疗“。总而言之，仍然需要一个GC 对新生儿BPD的药物治疗将有益于抗炎和肺成熟 效果，但不良反应有限，特别是在大脑中。因为啮齿动物新生儿容易患上 出生后sGC对神经发育的不利影响与人类相似，它们提供了一个机会 进行机械性研究，并确定目标和模式，以实现更具针对性的、新颖的sGC疗法。 环索奈德(CIC)是目前被批准用于治疗哮喘和过敏的新一代吸入型sGC。 鼻炎。它是一种前体药物，由成年人下呼吸道中丰富的羧酸酯酶(CESS)转化为 高效糖皮质激素激动剂地索丁酰环索奈德(DES-CIC) 受体。CIC被批准作为5岁及以上儿童的替代疗法，目前正在进行评估 在治疗2岁儿童变应性鼻炎的3期临床试验中。我们假设 新生儿接触sGC前体药物CIC不会引发脱髓鞘、星形胶质细胞增多症或小脑 地塞米松对新生儿的脑损伤，由于DES-CIC的蓄积和/或反应受限， CIC的活性代谢产物。该方案中的实验利用了一种新型的“人性化”基因敲除小鼠品系 这是为了更接近人类的CIC代谢而切除的血浆ES-1基因， 与啮齿动物不同的是，它们缺乏血浆CES。特定的目标将1)测量游离和脂肪酸的积累- 结合型DES-CIC在雌雄ES-1-/-小鼠不同新生组织中的表达及其个体发育 CES基因在新生儿脑和肺中的表达，以及2)脑内对CIC的活体生物反应 雄性和雌性ES-1-/-新生小鼠的肺组织。鉴于CIC在非常年轻的时候就已经建立了安全 对于儿童，我们提议的研究的临床翻译可以加快到人类新生儿， 特别是考虑到目前可用于治疗或预防BPD的安全治疗选择有限 在易感早产儿中。

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.