Optimal RNA-based therapeutics for vocal fold injury and fibrosis

描述（由申请人提供）：纤维化作为许多嗓音疾病的潜在病因的普遍性源于对损伤的修复反应。到目前为止，治疗在很大程度上不令人满意。认识到愈合是复杂的，我们寻求扩大我们最近的研究结果阐明一个监管机制修复声带。具体来说，我们寻求更多的洞察转化生长因子（TGF）-信号级联。我们的初步数据表明，靶向这一途径，而不是TGF-β直接，而是上游，是最佳的。Smad 3是一种上游细胞质信号传导蛋白，为使用基于RNA的治疗剂，特别是小干扰核糖核酸（siRNA）提供了理想的靶标。然而，siRNA在体内的递送由于固有的蛋白水解环境而变得复杂。我们假设脂质纳米粒递送将解决这些问题，提供最佳的药物浓度，降低毒性。这项调查是密切相关的;关于整个生命周期中嗓音障碍发生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多器官系统的临床。

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.