Pre Clinical and Clinical Development of a Novel Thiol-Saccharide Mucolytic

项目摘要 虽然阻塞呼吸道的病理性粘液是囊性肺炎症状和感染的主要原因 对于纤维化(CF)和其他肺部疾病，黏液溶解疗法目前在数量、疗效和 耐受性。加州大学旧金山分校和都柏林大学学院(UCD)最近的合作发现 氧化应激是粘液病理的关键机制，并为硫醇类药物作为新的药物提供了理论基础 粘液消毒剂。N-乙酰半胱氨酸(N-乙酰半胱氨酸[NAC])是一种有效的粘液剂，但作为吸入剂，它有很大的风险 治疗包括效力低、给药不便、呼吸道刺激、高挥发性和难闻气味。至 克服了这些问题，UCD的奥斯卡森博士通过以下方法合成了一类新型的硫醇疗法 对具有硫醇官能团的糖类进行修饰，以创建“硫醇-糖类”文库。这些小说 化合物对CF痰表现出显著的粘液溶解活性，起效快，效力高于NAC， 喷雾干燥粉末具有良好的加工性。重要的是，我们发现硫醇糖类没有表现出 在我们的呼吸道上皮细胞体外和体外研究中的先导性毒性研究中关于安全信号的任何问题 小鼠体内模型。所有这些数据使我们提出了三个目标，这将推动药物开发 硫醇-糖作为囊性纤维化的一种新的粘液溶解治疗方案。在目标1中，我们将确定和 从硫醇糖库中优化临床前候选化合物。在目标2中，我们将进行IND- 支持临床前研究，并为候选硫代糖的临床开发准备和归档IND 参见在AIM 3中，在IND清除方面，我们计划进行人类第一阶段1a单次递增剂量研究，以 评估吸入硫代糖治疗的初步安全性。我们将与多学科团队密切合作 参与此翻译计划项目的化学家、配方科学家、生物学家和临床医生 建议实现将硫醇修饰的碳水化合物推向临床以改善肺部健康的目标。

Project Summary Although pathologic mucus that obstructs the airways is a major cause of symptoms and infection in cystic fibrosis (CF) and other lung diseases, mucolytic therapies are currently limited in number, efficacy, and tolerability. Recent collaborative work between UCSF and University College Dublin (UCD) has uncovered oxidative stress as a key mechanism of mucus pathology and provided rationale for thiol-based drugs as novel mucolytics. N-acetyl cysteine [NAC]) is effective as a mucolytic, but it carries significant liabilities as an inhaled therapeutic including low potency, inconvenient administration, airway irritancy, high volatility and bad odor. To overcome these problems, Dr. Oscarson at UCD has synthesized a novel class of thiol-based therapeutics by modifying saccharides with thiol functionalities to create a library of “thiol-saccharides.” These novel compounds show significant mucolytic activity on CF sputum, fast onset of action, higher potency than NAC, and favorable processability as spray-dried powders. Importantly, we find that thiol-saccharides do not show any concerning safety signals in pilot toxicity studies in our studies on airway epithelial cells in vitro and in a mouse model in vivo. All of these data lead us to propose three Aims that will advance a drug development program for thiol-saccharides as a novel mucolytic treatment in cystic fibrosis. In AIM 1, we will identify and optimize the preclinical candidate compound from a library of thiol-saccharides. In AIM 2, we will conduct IND- enabling preclinical studies and prepare and file IND for clinical development of candidate thiol-saccharide in CF. In AIM 3, on IND clearance, we plan to conduct a first-in-human Phase 1a single ascending dose study to assess initial safety of inhaled thiol-saccharide therapeutic. We will work closely with the multidisciplinary team of chemists, formulation scientists, biologists and clinicians who are a part of this Translational Program Project proposal to achieve the goal of advancing a thiol-modified carbohydrate to the clinic to improve lung health.