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; 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.

项目摘要/摘要 成年美国人口中语音障碍的终生患病率为30％，点患病率 率为6.6％至7.5％1,2。点患病率和人口普查估计表明，近20-2300万成年人可能 每年经历吞咽困难，损失的工资接近130亿美元3。这些 年度直接成本与与慢性阻塞性肺部疾病，哮喘相关的成本相当 糖尿病和过敏性鼻炎3。这是改善语音障碍患者的护理仍然很重要的 公共卫生需求。为了满足这一需求，在过去的17年中，我们的研究计划启动了系统性 在理解细胞和分子病理生理学的研究中，声带组织会发生变化。 迄今为止，我们的研究为调节声音的细胞和分子序列提供了关键的新见解 折叠渗透性。在过去的五年中，我们将研究重点放在 语音疾病的药理治疗。我们的初步数据揭示了调节的机制 在大多数细胞中发现的一类类固醇激素的声带上皮屏障的渗透性 在人体中。除了这些糖皮质激素的抗炎作用之外，我们的出现证据 实验室支持糖皮质激素在调节声带细胞细胞途径中的作用。这些 初步数据导致了一个总体假设，即声带上皮渗透性可以是 使用针对细胞细胞途径的药物方法有选择地调节。这本小说 治疗概念通过提供人声折叠疾病的管理提供了令人兴奋的新可能性 药理学访问下层空间的通道，也是通用可用的跨越金属递送的手段 填充物和人声折叠的生物材料。在接下来的五年中，我们将融合下一个系列 研究性折叠上皮渗透性的选择性调节，结合体外 和体内实验。当前的R01建立在一系列调查的基础上 提供了必要的初步数据，以支持人声折叠旁途径的选择性渗透性。 该R01提案的目的是从经验上量化甲基丙糖酮对选择性调节的影响 人声折叠细胞路径。这些临床前研究对于提供使用的指示是必要的 安全性以及在人类试验之前的热效率的证明。项目的特定交付 完成将是在I/II/III期试验中进行严格测试所需的初步研究。