A single dose anti-scarring therapeutic for the cornea

单剂量角膜抗疤痕治疗剂

• 批准号: 10697582
• 负责人: Tere M. Williams
• 金额: $ 70万
• 依托单位: DUB BIOLOGICS, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-07-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697582
• 关键词: Adrenal Cortex Hormones; Adverse event; Affect; Apoptosis; Appearance; Area; Biological Products; Blindness; Cataract; Cells; Cellular Morphology; Cholesterol; Cicatrix; Clinical; Clinical Trials; Collagen; Computer software; Cornea; Corneal Injury; Cyclic GMP; Defect; Dermal; Disease; Dose; Drug toxicity; Economic Burden; Encapsulated; Environment; Epithelium; Eyedrops; Family suidae; Fiber; Fibroblasts; Fibronectins; Fluorescein; Formulation; Funding; Future; Glaucoma; Human; Immune; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Infection; Infection prevention; Inflammation; Inflammatory; Injury; Investigation; Investments; Keratoplasty; Legal patent; Length; Lipids; Marketing; Mediator; Methods; Modeling; Monocular Blindness; Mus; Nerve Regeneration; Organ Culture Techniques; Orphan Drugs; Oryctolagus cuniculus; Outcome; PTPRC gene; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Population; Preparation; Prevention; Preventive measure; Process; Proliferating; Quality of life; Resistance; Safety; Small Business Innovation Research Grant; Small Interfering RNA; Stains; Technology; Therapeutic; Therapeutic Clinical Trial; Tissues; Toxic effect; Toxicokinetics; Toxicology; Transfection; Transplantation; Trauma; Tubulin; Vision; Visual impairment; Visually Impaired Persons; Work; Wound models; animal efficacy; blind; cell type; combat; corneal epithelium; corneal scar; efficacy study; epithelial wound; experimental study; first-in-human; healing; improved; in vivo; in vivo Model; insight; knock-down; manufacture; manufacturing facility; manufacturing process; manufacturing run; manufacturing scale-up; monocular; mouse model; nanoparticle; neovascularization; novel; nuclease; pre-Investigational New Drug meeting; prevent; process optimization; regenerative; response; scale up; siRNA delivery; therapeutic siRNA; tissue repair; ubiquitin isopeptidase; wound closure; wound healing

Abstract DUB Biologics is developing a therapeutic for the prevention and treatment of corneal scarring through knockdown of a novel target that has been shown to be central to the fibrotic response leading to corneal opacification. Corneal opacification severely impairs the vision of 4.2 million people around the world, 5.1% of the total blind population. Monocular scarring is far more common, affecting 3x as many people. Scarring in the cornea resulting from injury, trauma, or infection can lead to debilitating opacities and permanent vision loss. Treatments to prevent scarring include corticosteroids however, they have unpredictable results and cause well- established adverse events that include cataracts and glaucoma. Once opacification occurs, it is most often irreversible and the only option for patients are corneal transplants. However, only 1 in every 80 corneas needed for transplant are available. Therefore, preventing opacification is of utmost importance. DUB Biologics has identified a novel scarring pathway in the cornea, central to which is the deubiquitinase USP10. USP10 activity in the cornea following injury can be modulated through knockdown of USP10 with a self-delivery siRNA (sdRNA). DUB Biologics’ drug is a fully modified sdRNA conjugated to a cholesterol moiety that does not need encapsulation for delivery. USP10-targeting sdRNA (sdUSP10) is effectively delivered to the cornea via eye drops. Additionally, sdUSP10 is resistant to nucleases, is not immunogenic, and demonstrates in vivo efficacy for months after a single treatment. Previous work has focused on mechanistic studies using human primary corneal stromal fibroblasts, corneal stromal wound healing models in mice and rabbits, and ex vivo pig organ culture. This Direct to Phase II SBIR project will advance sdUSP10 towards market launch through expansion of efficacy studies that will focus on persistence epithelial defect (PED) models in mice and rabbits and in human corneal organ culture. Based on comparable therapeutics in the ocular space, these will contribute significantly to the animal efficacy studies needed before first-in-human trials. In preparation for IND filing, the project will also support the demonstration of scaled-up production of human sdUSP10 in a GLP environment. The production runs will be used to conduct IND-enabling studies including toxicology and PK experiments in rabbits. At the conclusion of the project, DUB Biologics will have completed all required efficacy studies, created a scaled- up manufacturing process that is ready for cGMP conversion, and demonstrated the safety profile of sdUSP10. This will validate the technical viability of pursuing this therapeutic pipeline, enabling external investment to fund the remaining IND-enabling studies and conduct early-stage clinical trials. Creating a way to prevent PED and corneal scarring safely and effectively will improve the quality of life of millions of patients around the world and reduce the economic burden of corneal opacification and demand for corneal transplants.

抽象的 DUB Biologics 正在开发一种通过以下方式预防和治疗角膜疤痕的疗法： 一种新靶标，已被证明是导致角膜击倒的纤维化反应的核心 角膜混浊严重损害了全世界 420 万人的视力，占全球人口的 5.1%。 单眼疤痕的发病率是普通人群的 3 倍。 受伤、外伤或感染引起的角膜可能会导致视力下降和永久性视力丧失。 预防疤痕的治疗方法包括皮质类固醇，但它们的结果不可预测，并会导致严重的后果。 已确定的不良事件包括白内障和青光眼，一旦发生混浊，最常发生。 角膜移植是不可逆的，患者唯一的选择，然而，每 80 个角膜中只有 1 个需要移植。 因此，DUB Biologics 至关重要。 确定了角膜中一种新的疤痕形成途径，其核心是去泛素酶 USP10 活性。 损伤后的角膜可以通过自我递送 siRNA 敲低 USP10 来调节 (sdRNA)。 DUB Biologics 的药物是一种完全修饰的 sdRNA，与不需要的胆固醇部分缀合。 封装用于递送 USP10 靶向 sdRNA (sdUSP10) 通过眼睛有效递送至角膜。 此外，sdUSP10 对核酸酶具有抗性，不具有免疫原性，并且具有体内功效。 之前的工作主要集中在使用人类原发性的机制研究上。 角膜基质成纤维细胞、小鼠和兔角膜基质伤口愈合模型以及离体猪器官 这一直接进入第二阶段 SBIR 项目将通过扩展推动 sdUSP10 走向市场。 功效研究将重点关注小鼠、兔子以及人类的持续性上皮缺陷（PED）模型 基于眼部的类似治疗方法，这些将做出重大贡献。 为了准备 IND 申请，该项目将进行首次人体试验之前所需的动物功效研究。 还支持在 GLP 环境下大规模生产人 sdUSP10 的示范。 生产运行将用于进行 IND 支持的研究，包括兔子的毒理学和 PK 实验。 项目结束时，DUB Biologics 将完成所有必需的功效研究，创建规模化的- 建立了为 cGMP 转换做好准备的制造工艺，并展示了 sdUSP10 的安全性。 这将验证该治疗管道的技术可行性，从而使外部投资能够提供资金 剩余的 IND 支持研究并进行早期临床试验，创造一种预防 PED 和 安全有效的角膜疤痕治疗将改善全世界数百万患者的生活质量， 减少角膜混浊的经济负担和角膜移植的需求。