Aerosolized Vitamin A: Impact on Neonatal Lung Maturation, Hyperoxic Lung Injury and Bronchopulmonary Dysplasia

Coment Treateutics Inc.(Coment)是一家专注于开发、重新配制和 优化传统药物的交付，以解决服务不足的新生儿和 儿科患者群体。Coment正在开发其专有的优化水的气雾剂配方 混合维生素A棕榈酸酯用于早产儿非侵入性(吸入)分娩以解决维生素A缺乏症 (VaD)和相关的严重并发症，如支气管肺发育不良(BPD，本阶段的重点 I SBIR和此二期应用)、早产儿视网膜病变(ROP)和新生儿败血症--所有这些都很昂贵 并发症，发病率/死亡率很高。我们创新的吸入型(非侵入性剂量)维生素A配方 1)避免了侵入性肌肉内注射(IM)的缺点和当前口服形式的吸收限制， 克服更频繁地使用NICU的重大障碍，以及2)提供直接到目标器官的交付 为了提高疗效，我们的I期体内数据显示，与肌注剂量相比，在缓解 高氧性肺损伤(我们的BPD动物模型)，同时提供足够的全身给药来治疗VAD。 在与港湾-加州大学洛杉矶分校医学中心的Virender Rehan博士的合作下，我们已经完成了我们的阶段 1)吸入维生素A可刺激肺成熟，如通过肺测定证明的那样。 显示视黄醇受体、表面活性蛋白和磷脂合成上调的生物标志物 成熟的生物标志物，同时提高血清维生素A水平，类似于肌注剂量；和2)吸入维生素A 通过肺组织形态计量学和肺组织形态计量学检查，(VS IM)显著减轻高氧性肺组织损伤 肺损伤生物标志物的减少。 在第二阶段，我们将进一步完善吸入维生素A的剂量策略，以减轻高氧肺损伤 循序渐进的方法，通过研究特征良好的预断奶大鼠模型，如在第一阶段，然后扩展 我们对早产兔模型的研究，其肺成熟状态更接近于人类早产儿 以便将我们的发现转化为临床应用。第二阶段的具体目标是：1：优化剂量 雾化维生素A方案减轻新生大鼠模型高氧性肺损伤 (急性期)和长期后遗症(慢性期)使用相似的生物标志物和形态 根据阶段I进行评估目标2：将吸入维生素A的急性期和慢性期益处扩大到早产儿 兔子模型。目标1和2成功的措施将是改善肺成熟和缓解的示范 与IM剂量的对照组相比，理想的结果是显示出与健康正常相似的肺状态 控制。目标3：优化气雾剂特性/传递(与AIM同时进行的初步体外实验 1)，并随后进行体内启用IND的毒理学/PK研究。衡量成功的目标3将是 数据的生成支持进一步开发潜在的更好的、非侵入性的预防治疗方法 BPD(和治疗VAD)，这将具有重大的临床、财政和社会影响。

Advent Therapeutics Inc. (Advent) is a biotech company focusing on the development, reformulation and optimized delivery of legacy drugs to address serious unmet medical needs in the underserved neonatal and pediatric patient populations. Advent is developing an aerosol formulation of its proprietary, optimized water miscible vitamin A (vitA) palmitate for non-invasive (inhaled) delivery to preterm infants to address vitA deficiency (VAD) and associated serious complications such as bronchopulmonary dysplasia (BPD, the focus of our Phase I SBIR and this Phase II application), retinopathy of prematurity (ROP), and neonatal sepsis – all costly complications with significant morbidity/mortality. Our innovative inhaled (non-invasively dosed) vitA formulation 1) avoids the drawbacks of invasive intramuscular (IM) injections and absorption limitations of current oral forms, overcoming significant hurdles to more frequent NICU utilization, and 2) provides direct-to-target-organ delivery for increased efficacy, with our Phase I in vivo data showing significant benefit over IM dosing in mitigating hyperoxic lung damage (our BPD animal model), while providing adequate systemic delivery to also treat VAD. In collaboration with Dr. Virender Rehan at Harbor-UCLA Medical Center, we have accomplished our Phase I Specific Aims, demonstrating that: 1) inhaled vitA stimulates lung maturation as demonstrated via assay of lung biomarkers showing upregulation of retinol receptors, surfactant protein and phospholipid synthesis, and maturation biomarkers while simultaneously raising serum vitA levels similar to IM dosing; and 2) inhaled vitA dramatically (vs IM) reduces hyperoxic lung tissue damage via examination of lung tissue histomorphometry and reduction of lung-injury biomarkers. In Phase II, we will further refine the inhaled vitA dosing strategy for mitigating hyperoxic lung damage in a step-wise approach by studying the well characterized pre-weaned rat model as in Phase I and then expanding our studies to a pre-term rabbit model, with lung maturation status more closely mimicking human preterm infant lung to allow for translation of our findings into the clinical. Phase II Specific Aims are: 1: Optimize the dosing regimen of aerosolized vitA for mitigating hyperoxic lung damage in our rat model for the “neonatal” timeframe (acute phase) and long term sequalae into adulthood (chronic phase) using similar biomarkers and morphologic evaluation as per Phase I. Aim 2: Extend acute and chronic phase benefits of inhaled vitA to the premature rabbit model. Aim 1 & 2 measures of success will be demonstration of improved lung maturation and mitigation of lung injury vs IM-dosed controls, with an ideal outcome of showing lung status similar to healthy normal controls. Aim 3: Optimize aerosol characterization/delivery (initial in vitro experiments done concurrent with Aim 1), and subsequently conduct in vivo IND-enabling toxicology/PK studies. Aim 3 measures of success will be generation of data supporting further development of a potentially superior, non-invasive therapy for preventing BPD (and treating VAD), which will have significant clinical, financial, and societal implications.