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

雾化维生素 A：对新生儿肺成熟、高氧性肺损伤和支气管肺发育不良的影响

• 批准号: 10238056
• 负责人: Craig Gelfand
• 金额: $ 127.07万
• 依托单位: ADVENT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238056
• 关键词: Acute; Address; Adult; Aerosols; All-Trans-Retinol; Animal Model; Biochemistry; Biological Assay; Biological Markers; Biotechnology; Bronchopulmonary Dysplasia; Chronic Phase; Chronic lung disease; Clinical; Clinical Trials; Collaborations; Confidential Information; Data; Development; Dose; Drug Delivery Systems; Effectiveness; Enteral; Evaluation; FDA approved; Formulation; Funding; Future; Generations; Goals; Human; Hyperoxia; In Vitro; Industry Standard; Inhalation; Injections; Intramuscular; Intramuscular Injections; Lung; Lung diseases; Measures; Medical; Medical center; Metabolic; Modeling; Morbidity - disease rate; Morphology; National Heart, Lung, and Blood Institute; Neonatal; Neonatal Hyperoxic Injury; Oral; Organ; Orphan; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Economics; Pharmaceutical Preparations; Phase; Phospholipids; Population; Positioning Attribute; Premature Birth; Premature Infant; Prevention; Program Development; Proteins; Pulmonary Surfactants; Pulmonary function tests; Rattus; Regimen; Retinopathy of Prematurity; Risk; Sepsis; Serum; Severities; Small Business Innovation Research Grant; Structure of parenchyma of lung; Sum; Supplementation; Survival Rate; Testing; Therapeutic; Tissues; Toxicology; Translations; Up-Regulation; Vitamin A; Vitamin A Deficiency; Water; Weaning; Work; absorption; aerosolized; clinical application; cost; design; drug development; experimental study; first-in-human; improved; in vivo; innovation; interest; lung injury; lung maturation; mortality; neonatal patient; neonatal sepsis; normoxia; novel strategies; patient population; pediatric patients; postnatal; premature; premature lungs; preterm newborn; prevent; product development; programs; pulmonary function; receptor; retinyl palmitate; specific biomarkers; success; surfactant

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.

Advent Therapeutics Inc.（Advent）是一家生物技术公司，专注于开发，重新制作和 优化遗留药物的递送，以解决未满足的新生儿中的严重未满足医疗需求 小儿患者人群。 Advent正在开发其专有，优化水的气溶胶公式 可混杂的维生素A（VITA）棕榈酸酯，用于非侵入性（吸入）向早产儿的分娩，以解决Vita缺乏症 （VAD）和相关的严重并发症，例如支气管肺发育不良（BPD，我们阶段的重点 I SBIR和此II期应用程序），早产视网膜病变（ROP）和新生儿败血症 - 都昂贵 并发症具有明显的发病率/死亡率。我们创新的继承（非侵入性）Vita公式 1）避免肌肉内（IM）注射和当前口服形式的滥用限制的缺点， 克服更频繁的NICU利用率的重大障碍，2）提供直接靶向器官交付 为提高效率，我们的I阶段IN VIVO数据显示出在减轻剂量方面的重大好处 高氧性肺损伤（我们的BPD动物模型），同时提供足够的全身性传递来治疗VAD。 与Harbour-Ucla医疗中心的Virender Rehan博士合作，我们完成了阶段 我的特定目的，证明：1）遗传的Vita刺激肺成熟，如肺的测定所证明 出现视黄醇受体，表面活性剂蛋白和磷脂合成的生物标志物，以及 成熟生物标志物，同时提高血清维塔水平，类似于我的给药； 2）继承的维塔 通过检查肺组织组形态和 减少肺部生物标志物。 在第二阶段，我们将进一步完善遗传的Vita给药策略，以减轻A中的高氧肺损伤 通过研究阶段I的表征良好的预性大鼠模型，然后扩展，逐步方法 我们对兔子前模型的研究，肺部成熟状态更亲密地模仿人类早产 肺部可以将我们的发现转化为临床。 II阶段特定目标是：1：优化剂量 在“新生儿”的大鼠模型中，在我们的大鼠模型中减轻高氧肺损害的雾化vita方案 （急性期）和长期序列段进入成年（慢性期），使用类似的生物标志物和形态学 根据第1阶 兔子模型。目标1和2的成功度量将证明改善肺部成熟和缓解措施 肺部损伤与正在剂量的对照，其理想结果表现出类似于健康正常状态的肺状况 控件。 AIM 3：优化气溶胶表征/传递（初始体外实验与AIM进行同时进行 1），随后进行体内毒理学/PK研究。 AIM 3成功的措施将是 生成支持进一步开发潜在的非侵入性疗法的数据 BPD（以及VAD）将具有重大的临床，财务和社会影响。