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

Advent Therapeutics Inc（降临）是一家生物技术公司，专注于开发，重新制定和 优化传统药物的交付，以解决服务不足的新生儿和 儿科患者人群。Advent正在开发其专有的优化水的气雾剂配方 用于非侵入性（吸入）递送给早产儿以解决维生素A缺乏症的可混溶维生素A（维生素A）棕榈酸酯 (VAD)和相关的严重并发症，如支气管肺发育不良（BPD，我们阶段的重点 I SBIR和该II期应用）、早产儿视网膜病变（ROP）和新生儿败血症-所有这些都是昂贵的 具有显著发病率/死亡率的并发症。我们的创新吸入（非侵入性给药）vitA配方 1)避免了侵入性肌内（IM）注射和当前口服形式的吸收限制的缺点， 克服了更频繁使用NICU的重大障碍，以及2）提供直接靶器官递送 为了提高疗效，我们的I期体内数据显示，与IM给药相比， 高氧肺损伤（我们的BPD动物模型），同时提供足够的全身递送也治疗VAD。 在与Harbor-UCLA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 I特定目的，证明：1）吸入维生素A刺激肺成熟，如通过肺成熟试验所证明的。 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，和 成熟生物标志物，同时提高血清维生素A水平，类似于IM给药;和2）吸入维生素A 通过肺组织形态计量学检查，显著（与IM相比）减少高氧肺组织损伤， 减少肺损伤生物标志物。 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， 通过研究I期中充分表征的断奶前大鼠模型，然后扩展 我们的研究是在早产兔模型上进行的，其肺成熟状态更接近于人类早产儿 肺，以便将我们的发现转化为临床。第二阶段的具体目标是：1：优化剂量 雾化维生素A方案减轻大鼠模型“新生儿”时间段的高氧肺损伤 使用相似的生物标志物和形态学特征， 按照第一阶段进行评估。目的2：将吸入维生素A的急性和慢性期益处扩展到早产儿 兔子模型目标1和2成功的衡量标准将是证明肺成熟和缓解的改善 肺损伤与IM给药对照组相比，具有显示肺状态与健康正常相似的理想结局 对照目标3：优化气雾剂表征/递送（与目标同时进行的初始体外实验 1），随后进行体内IND使能毒理学/PK研究。目标3衡量成功的标准将是 生成支持进一步开发潜在的上级、非侵入性治疗的数据， BPD（和治疗VAD），这将具有重大的临床，财务和社会影响。

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.