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.

摘要 DUB Biologics正在开发一种用于预防和治疗角膜瘢痕的治疗方法， 一种新靶点的敲除已被证明是导致角膜纤维化的纤维化反应的核心， 不透明化角膜混浊严重损害了全球420万人的视力， 全盲人口。单眼疤痕更为常见，影响的人数是三倍。瘢痕 由损伤、创伤或感染引起的角膜可导致使人衰弱的混浊和永久性视力丧失。 预防瘢痕形成的治疗包括皮质类固醇，然而，它们具有不可预测的结果，并导致- 包括白内障和青光眼在内的已确定的不良事件。一旦发生混浊， 这是不可逆的，患者的唯一选择是角膜移植。然而，每80个角膜中只有1个需要 可供移植。因此，防止不透明化至关重要。DUB Biologics拥有 确定了角膜中的一种新的瘢痕形成途径，其中心是去泛素化酶USP 10。USP 10活性 可以通过用自递送siRNA敲低USP 10来调节损伤后角膜中的 （sdRNA）。DUB Biologics的药物是一种完全修饰的sdRNA，与胆固醇部分结合， 用于递送的封装。USP 10靶向sdRNA（sdUSP 10）通过眼睛有效递送至角膜 滴剂.此外，sdUSP 10对核酸酶具有抗性，无免疫原性，并显示出体内疗效 几个月后，一个单一的治疗。以前的工作主要集中在使用人类初级 角膜基质成纤维细胞、小鼠和兔的角膜基质伤口愈合模型以及离体猪器官 文化该直接进入第二阶段SBIR项目将通过扩展 疗效研究，重点关注小鼠、家兔和人体持续性上皮缺损（PED）模型 角膜器官培养基于眼内空间的可比治疗，这些将显著有助于 在首次人体试验之前需要进行动物疗效研究。为了准备IND申请，该项目将 还支持在GLP环境中规模化生产人sdUSP 10的证明。的 生产运行将用于进行IND启用研究，包括家兔毒理学和PK实验。 在项目结束时，DUB Biologics将完成所有要求的疗效研究，创建一个规模化的- 生产工艺已准备好进行cGMP转换，并证明了sdUSP 10的安全性。 这将验证追求这一治疗管道的技术可行性，使外部投资能够资助 其余的IND使能研究，并进行早期临床试验。创造一种防止PED的方法， 安全有效地形成角膜瘢痕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对角膜移植的需求。