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Optimal RNA-based therapeutics for vocal fold injury and fibrosis

针对声带损伤和纤维化的最佳 RNA 疗法

基本信息

批准号：
8762049
负责人：
Ryan Comfort Branski
金额：
$ 42.1万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-19 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762049
关键词：
Acute Address Affect American Biological Biomechanics Cell Proliferation Cells Chronic Obstructive Airway Disease Cicatrix Clinic Clinical Clinical Treatment Collagen Complex Data Deposition Development Diffuse Direct Costs Disease Distant Environment Etiology Extracellular Matrix Fibroblasts Fibrosis Financial cost Gel Gene Silencing Goals Healed Human In Vitro Incidence Income Injection of therapeutic agent Injury Intervention Investigation Lamina Propria Lesion Lipids Longevity Maintenance Mediator of activation protein Mental Depression Messenger RNA Metabolism Modeling Nodule Occupational Operative Surgical Procedures Organ Oryctolagus cuniculus Pathway interactions Patients Pharmaceutical Preparations Phenotype Phonation Pliability Population Process Proteins RNA Reagent Research Personnel Role Signal Transduction Signaling Protein Small Interfering RNA Social Functioning Source Stenosis Techniques Testing Therapeutic Therapeutic Effect Tissues Toxic effect Transcriptional Regulation Transfection Transforming Growth Factors Treatment Protocols Up-Regulation Voice Voice Disorders Work Wound Healing base body system cytotoxicity experience healing human MADH3 protein improved in vivo injured innovation insight interest migration nanoparticle novel public health relevance regenerative repaired response response to injury stem therapeutic target tissue repair vocal cord vocalis muscle

项目摘要

DESCRIPTION (provided by applicant): The universality of fibrosis as an underlying etiology for many voice disorders stems from the reparative response to injury. To date, treatments have been largely unsatisfactory. Acknowledging that healing is complex, we seek to expand our recent findings elucidating one regulatory mechanism underlying repair in the vocal folds. Specifically, we seek increased insight into the transforming growth factor (TGF)-¿ signaling cascade. Our preliminary data suggest that targeting this pathway, not TGF-¿ directly, but rather upstream, to be optimal. Smad3, an upstream cytoplasmic signaling protein provides an ideal target for the use of RNA- based therapeutics, specifically small interfering ribonucleic acid (siRNA). However, delivery of siRNA in vivo is complicated by the inherent proteolytic environment. We hypothesize that lipid nanoparticle delivery will address these issues, delivering optimal drug concentrations with reduced toxicity. This investigation is germane; cumulative estimates regarding the incidence of voice disorders across the lifespan are not known, but are hypothesized to be higher than the 3-9% of the population figure that is often cited. This innovative approach has potential to evolve to the clinic across multiple organ systems.

描述(由申请人提供)：纤维化作为许多发音障碍的潜在病因的普遍性源于对损伤的修复反应。到目前为止，治疗方法在很大程度上并不令人满意。认识到修复是复杂的，我们试图扩大我们最近的发现，阐明声带修复背后的一种调节机制。具体地说，我们寻求对转化生长因子(TGF)-β信号级联的更深入的了解。我们的初步数据表明，以这一途径为靶点，而不是直接针对转化生长因子β，而是针对上游，是最优的。Smad3是一种上游的细胞质信号蛋白，为基于RNA的疗法，特别是小干扰核糖核酸(SiRNA)的使用提供了理想的靶点。然而，体内siRNA的传递因其固有的蛋白分解环境而变得复杂。我们假设脂质纳米粒传递将解决这些问题，以降低毒性传递最佳药物浓度。这项调查是密切相关的；关于一生中嗓音障碍发病率的累积估计尚不清楚，但假设高于经常引用的人口数字的3%-9%。这种创新的方法有可能发展到跨多个器官系统的临床。