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

I-Corps：抗纤维化自传递 siRNA 疗法

• 批准号: 2325526
• 负责人: Audrey Bernstein
• 金额: $ 5万
• 依托单位: SUNY, Upstate Medical University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2325526&HistoricalAwards=false
• 关键词: Corps; Anti; Fibrotic; Self; Delivering

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.

该 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，可促进愈合并显着减少疤痕。 纤维化和疤痕是过量细胞外基质成分的积累，是包括硬皮病和心、肺、肝、角膜和皮肤纤维化在内的多种临床适应症的病理成分。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。所提议技术的最初重点是角膜和真皮疤痕。角膜和皮肤具有相似的治疗方式，即施用局部溶液。角膜和皮肤可以作为研究所有组织中纤维化病理学的模型组织，并可能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。 I-Corps 项目基于开发一种自我递送 siRNA 治疗方法，以预防疤痕和纤维化。已经确定了一个基因靶点，可以减缓病变并支持受伤角膜和皮肤（两种纤维化模型组织）的再生愈合。数据显示，角膜和皮肤受伤模型中的目标敲除可促进再生愈合，这是一种有限甚至无疤痕的伤口愈合。目前的护理标准是对伤口（角膜和皮肤）局部施用类固醇，会产生不可预测的混合结果，其在愈合率提高、无效或愈合率降低之间差异很大。所提出的技术使用 siRNA 的局部给药，该 siRNA 可有效渗透细胞，并作为局部伤口的抗炎剂和抗疤痕剂。所提出的治疗方法经过优化，可以穿透组织，单次剂量的疗效可持续 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，小型和大型动物模型的体内结果证明了疗效，并且还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，并被视为值得通过使用基金会的智力优点和更广泛的影响审查标准进行评估来支持。