Pharmacological Approaches for Transepithelial Delivery of Therapeutics to the Vocal Folds

跨上皮递送治疗药物至声带的药理学方法

• 批准号: 10675188
• 负责人: Bernard Rousseau
• 金额: $ 54万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675188
• 关键词: Pharmacological; Approaches; Transepithelial; Delivery; Therapeutics

PROJECT SUMMARY/ABSTRACT The lifetime prevalence of voice disorders in the adult United States population is 30% with point prevalence rates of 6.6% to 7.5%1,2. Point prevalence and census estimates suggest that nearly 20-23 million adults may experience dysphonia annually, with the cost of treatment and lost wages approaching $13 billion dollars3. These annual direct costs are comparable to those associated with chronic obstructive pulmonary disease, asthma, diabetes, and allergic rhinitis3. Thus, improving the care of patients with voice disorders remains a significant public health need. To address this need, over the last 17 years, our research program has initiated systematic studies in the understanding of the cellular and molecular pathophysiology underlying vocal fold tissue changes. Our studies to date have provided critical new insights into the cellular and molecular sequalae regulating vocal fold permeability. Over the last 5 years, we have focused our studies on the safety and efficacy of pharmacological treatments for voice disorders. Our preliminary data have revealed mechanisms regulating permeability of the vocal fold epithelial barrier from a class of steroid hormones ubiquitously found in most cells in the human body. Beyond the anti-inflammatory actions of these glucocorticoids, emerging evidence in our laboratory supports a role for glucocorticoids in the regulation of the vocal fold paracellular pathway. These preliminary data have led to an overarching hypothesis that vocal fold epithelial permeability can be selectively regulated using pharmacological approaches that target the paracellular pathway. This novel treatment concept provides exciting new possibilities in the management of vocal fold disease by providing pharmacologic access to the subepithelial space–and a means for transepithelial delivery of commonly available fillers and biomaterials to the vocal folds. Over the next five years, we will converge our next series of studies on the selective regulation of vocal fold epithelial permeability using a combination of in vitro and in vivo experiments. The current R01 builds on a programmatic series of investigations which have provided the necessary preliminary data to support selective permeability of the vocal fold paracellular pathway. The goal of this R01 proposal is to empirically quantify the effects of methylprednisolone on selective regulation of the vocal fold paracellular pathway. These pre-clinical studies are necessary to provide indications for use, safety, and the demonstration of therapeutic efficacy prior to human trials. The specific deliverable upon project completion will be the preliminary studies necessary for rigorous testing in phase I/II/III human trials.

项目总结/摘要 美国成年人嗓音障碍的终生患病率为30%， 6.6%至7.5%的比率1，2.点患病率和人口普查估计表明，近20-23百万成年人可能 每年经历发音困难，治疗费用和工资损失接近130亿美元3。这些 每年的直接成本与慢性阻塞性肺病，哮喘， 糖尿病和过敏性鼻炎3.因此，改善嗓音障碍患者的护理仍然是一个重要的问题。 公共卫生需要。为了满足这一需求，在过去的17年里，我们的研究计划启动了系统的 研究声带组织变化背后的细胞和分子病理生理学。 迄今为止，我们的研究为调节发声的细胞和分子后遗症提供了重要的新见解 倍渗透率在过去的5年里，我们的研究重点是安全性和有效性， 药物治疗声音障碍。我们的初步数据显示， 声带上皮屏障对一种普遍存在于大多数细胞中的类固醇激素的通透性 在人体内。除了这些糖皮质激素的抗炎作用，我们的研究中出现的证据表明， 实验室支持糖皮质激素在调节声带旁细胞途径中的作用。这些 初步的数据已经导致了一个总体假设，即声带上皮的通透性可以是 使用靶向细胞旁途径的药理学方法选择性调节。这本小说 治疗概念提供了令人兴奋的新的可能性，在声带疾病的管理， 药物进入上皮下空间-和一种用于经上皮递送通常可获得的药物的手段， 填充物和生物材料在接下来的五年里，我们将汇集我们的下一系列 体外联合应用选择性调节声带上皮通透性的研究 和体内实验。目前的R 01建立在一系列有计划的调查基础上， 提供了必要的初步数据来支持声带细胞旁途径的选择性渗透性。 R 01提案的目的是根据经验量化甲基强的松龙对选择性调节的影响 声带旁细胞通路的一个重要组成部分。这些临床前研究对于提供使用适应症是必要的， 安全性，以及在人体试验之前证明治疗功效。项目的具体交付成果 完成的将是I/II/III期人体试验严格测试所需的初步研究。