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

这个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，其是广泛的临床适应症的病理学成分，包括硬皮病和心脏、肺、肝、角膜和皮肤的纤维化。大约三分之一的死亡与纤维化结果有关，这是一个重大问题和市场机会。所提出的技术的最初重点是角膜和皮肤疤痕。角膜和皮肤具有通过施用局部溶液的类似治疗模式。角膜和皮肤可以作为研究所有组织中纤维化病理生物学的模型组织，并且可能导致扩展到具有纤维化基础的其他适应症，例如肺纤维化、非酒精性脂肪性肝炎（NASH）、心血管疾病和神经退行性疾病。已经确定了一种遗传靶点，它可以减缓病理学并支持受伤的角膜和皮肤（两种纤维化模型组织）的再生愈合。数据显示，角膜和皮肤创伤模型中的靶点敲除促进再生愈合，这是一种有限至无瘢痕的伤口愈合。目前的护理标准，即对伤口（角膜和皮肤）局部施用类固醇，产生不可预测的混合结果，其在愈合率增加、无效或愈合率降低之间变化很大。所提出的技术使用siRNA的局部施用，所述siRNA有效地穿透细胞并且用作局部伤口的抗炎剂和抗瘢痕形成剂。所提出的治疗剂被优化以渗透组织，并且被设计为单剂量有效2-3个月，这可能会彻底改变视网膜下瘢痕形成和全身性纤维化疾病。此外，在小型和大型动物模型中的体内试验结果证明了其有效性，并呈现出良好的安全性，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NSF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.