I-Corps: Anti-Fibrotic Self-Delivering siRNA Therapeutics

I-Corps项目更广泛的影响/商业潜力是开发一种潜在的治疗方法，促进愈合，显著减少疤痕。纤维化和瘢痕形成是过量细胞外基质成分的积累，是广泛的临床适应症的病理成分，包括硬皮病和心脏、肺、肝脏、角膜和皮肤的纤维化。大约三分之一的死亡与纤维化有关，这是一个重大问题和市场机会。提出的技术最初的重点是角膜和真皮疤痕。角膜和皮肤有一个类似的治疗方式，通过局部溶液的管理。角膜和皮肤可作为研究所有组织纤维化病理生物学的模型组织，并可扩展到其他纤维化基础适应症，如肺纤维化、非酒精性脂肪性肝炎（NASH）、心血管疾病和神经退行性疾病。I-Corps项目的基础是开发一种自我递送的siRNA治疗方法，以防止疤痕和纤维化。已经确定了一种基因靶点，可以减缓病理并支持角膜和皮肤损伤的再生愈合，这是两种纤维化的模型组织。数据显示，在角膜和皮肤损伤模型中，靶标敲除促进再生愈合，这是一种有限或无疤痕的伤口愈合。目前的护理标准是在伤口（角膜和皮肤）局部施用类固醇，其结果不可预测且好坏参半，在增加愈合率、没有效果或降低愈合率之间差异很大。提出的技术使用局部施用的siRNA，有效地穿透细胞，并作为局部伤口的抗炎和抗疤痕剂。所提出的治疗方法被优化为穿透组织，单次剂量有效2-3个月，这可能会彻底改变视网膜下疤痕和系统性纤维化疾病。此外，在小型和大型动物模型中的体内结果显示出有效性和良好的安全性，没有细胞/组织毒性的证据，这可能导致疤痕和纤维化的治疗。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of a potential therapeutic treatment that promotes healing with significantly decreased scarring. Fibrosis and scarring are the accumulation of excess extracellular matrix components, which is a pathological component of a wide spectrum of clinical indications including scleroderma and fibrosis of the heart, lung, liver, cornea, and skin. Approximately one-third of all fatalities are associated with fibrotic outcomes, which represents a significant problem and market opportunity. The initial focus of the proposed technology is corneal and dermal scarring. Cornea and skin have a similar treatment modality by administration of a topical solution. Cornea and skin may serve as model tissues for studying the pathobiology of fibrosis in all tissues, and may lead to expansion into other indications with fibrotic underpinnings such as pulmonary fibrosis, non-Alcoholic Steatohepatitis (NASH), cardiovascular disease, and neurodegenerative diseases.This I-Corps project is based on the development of a self-delivery siRNA therapeutic treatment to prevent scarring and fibrosis. A genetic target has been identified that slows pathology and supports regenerative healing of wounded cornea and skin, two model tissues of fibrosis. Data show target knockdown in corneal and skin wounding models promotes regenerative healing, a type of wound healing with limited to no scarring. The current standard of care, topical administration of steroids to wounds (cornea and skin), yields unpredictable, mixed results, that vary widely between increased rates of healing, no effect, or decreased healing rates. The proposed technology uses topical administration of a siRNA that effectively penetrates cells and functions as both an anti-inflammatory and anti-scarring agent for topical wounds. The proposed therapeutic is optimized to penetrate tissues and is designed to be efficacious for 2-3 months with a single dose, which may revolutionize subretinal scarring and systemic fibrotic diseases. In addition, in vivo results in small and large animal models demonstrate efficacy and also present favorable safety profiles with no evidence of cellular/tissue toxicity, which may lead to a treatment for scarring and fibrosis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.