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 配音生物制剂正在开发一种治疗性，用于预防和治疗通过 击倒一个新目标，该目标已被证明是导致角膜的纤维化反应的核心 卵子化。角膜OOpacification严重损害了全球420万人的愿景，占5.1％ 盲人总人口。单眼疤痕更为普遍，影响了3倍。在 因受伤，创伤或感染而导致的角膜会导致衰弱和永久视力丧失。 防止疤痕的治疗方法包括皮质类固醇，但是它们的结果不可预测并引起良好 已建立的不良事件，包括白内障和青光眼。一旦发生不透明，它通常是 不可逆的，唯一的选择是角膜移植。但是，每80个角膜中只需要1个 用于移植。因此，防止职业至关重要。配音生物制剂 确定了角膜中的一种新颖的疤痕途径，中心是去泛素酶USP10。 USP10活动 在受伤后的角膜中，可以通过使用自传递的siRNA来调节USP10 （SDRNA）。配音生物制剂的药物是连接到不需要的胆固醇部分的完全修饰的SDRNA 交付的封装。 USP10靶向SDRNA（SDUSP10）通过眼睛有效地传递到角膜 滴。此外，SDUSP10对核素具有抗性，不是免疫原性的，并且在体内效率表明 一次治疗后的几个月。以前的工作重点是使用人类原则的机械研究 角膜基质成纤维细胞，小鼠和兔子中的角膜基质伤口愈合模型以及离体猪器官 文化。直接到II阶段SBIR项目将通过扩展将SDUSP10推向市场推出 功效研究将重点介绍小鼠和兔子的持久性上皮缺陷（PED）模型以及人类 角膜器官文化。基于眼部空间中的可比较疗法，这些将显着贡献 在第一次人类试验之前需要进行的动物效率研究。为了准备IND提交，该项目将 还支持GLP环境中人类SDUSP10扩大生产的演示。这 生产运行将用于进行辅助研究，包括兔子中的毒理学和PK实验。 在项目结束时，配音生物制剂将完成所有必需的效率研究，并创建一个缩放 提高准备CGMP转换的制造过程，并证明了SDUSP10的安全性。 这将验证追求该治疗管道的技术可行性，使外部投资能够提供资金 其余的辅助研究并进行早期临床试验。创建一种防止PED和 安全有效的角膜疤痕将改善世界各地数百万患者的生活质量 减少角膜不透明的经济燃烧和对角膜移植的需求。