A single dose anti-scarring therapeutic for the cornea

摘要 DUB Biologics正在开发一种用于预防和治疗角膜瘢痕形成的疗法 一种新的靶点被击倒，该靶点被证明是导致角膜纤维化反应的中心 混浊。角膜混浊严重损害了全球420万人的视力，5.1%的人 失明人口总数。单眼疤痕要常见得多，影响人数是普通人的3倍。伤痕累累 由损伤、创伤或感染引起的角膜可导致衰弱混浊和永久性视力丧失。 防止疤痕形成的治疗方法包括皮质类固醇，然而，它们的结果不可预测，并导致良好的- 已确定的不良事件包括白内障和青光眼。一旦发生浑浊，最常见的是 不可逆转的，患者唯一的选择是角膜移植。然而，每80个角膜中只有1个需要 可供移植。因此，防止不透明是最重要的。Dub Biologics有 在角膜中发现了一种新的疤痕形成途径，其中心是脱泛素酶USP10。USP10活动 在角膜损伤后，可通过自身递送的siRNA敲除USP10来调节 (SdRNA)。Dub Biologics的药物是一种完全修饰的sdRNA，连接到不需要的胆固醇部分 用于交付的封装。USP10靶向sdRNA(SdUSP10)通过眼睛有效地输送到角膜 水滴。此外，sdUSP10对核酸酶具有抵抗力，不具有免疫原性，并显示出体内的有效性。 在一次治疗后的几个月里。以前的工作主要集中在使用人类初级生物的机械学研究上 角膜基质成纤维细胞，小鼠和兔角膜基质创伤愈合模型，以及体外猪器官 文化。这一直接到第二阶段的SBIR项目将通过扩展 疗效研究将集中在持续性上皮缺陷(PED)模型在小鼠、兔和人身上 角膜器官培养。基于眼球空间的可比疗法，这些将做出重大贡献。 在第一次人体试验之前所需的动物功效研究。在为IND备案做准备时，该项目将 还支持在GLP环境中演示人类sdUSP10的放大生产。这个 生产运行将用于在兔子身上进行IND研究，包括毒理学和PK实验。 在项目结束时，DUB Biologics将完成所有必要的疗效研究，创建一个规模- 为cGMP转换做好准备的UP制造工艺，并展示了sdUSP10的安全概况。 这将验证追求这一治疗渠道的技术可行性，使外部投资能够提供资金 其余的IND使能研究并进行早期临床试验。创造了一种预防PED和 安全有效的角膜疤痕形成将改善全球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。

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.