Protection and Treatment of the Ocular Surface Barrier

 描述(申请人提供)：干眼症是一组疾病，目前在美国影响着约500万50岁以上的人，其特征是眼表水分和润滑剂不足。所有类型干眼的最终共同途径是破坏眼表面屏障，这可以通过量化局部应用于眼表面的水溶性染料的摄取量来评估。在使用临床前模型的初步数据中，研究表明，局部注射簇蛋白(CLU)，一种天然的体内平衡泪液蛋白，通过依赖于达到关键的全有或无阈值的显著封闭机制，防止和改善临床前模型中的屏障破坏。CLU的抗炎、蛋白抑制和细胞保护作用是众所周知的。结果表明，CLU选择性地结合在干燥应力作用下的眼表面，并以这种方式定位，也保护了屏障结构。Proteris Biotech，Inc.的长期目标是将CLU转化为FDA批准的生物疗法用于临床。这项第一阶段的STTR应用有两个直接的科学目标：1)在非GMP条件下，建立和执行与良好制造规范(GMP)兼容的人类重组形式的CLU，称为“蛋白质素”；2)证明蛋白质素在功能上与人血浆来源的CLU相同，并比较其与两种参考化合物的疗效。此外，还将执行STTR第二阶段的规划活动，包括：1)编写协议，将蛋白质生产过程转移到GMP实验室，并适应GMP合规性；2)为GMP生产的蛋白质的良好实验室(GLP)测试确定合格的分包商；3)为蛋白质素的“首例人类”I期临床试验编写协议，目标是评估产品安全性并提供人体疗效的主要证据；4)招募合作者/顾问，并为执行这些后续步骤寻找新的实验室空间。在DE领域，新药开发的大部分努力都致力于针对炎症、泪液产生、泪膜运动和泪液化学，即位于导致DE和OCS中断的一系列事件的上游因素。这些因素不同，干眼症的类型也不同。CLU在OCS的密封作用尚未对任何其他正在开发的药物进行描述。一种可以针对干眼上游因素的治疗方法，以及最终共同终点屏障破坏，代表了一项重要的创新。

 DESCRIPTION (provided by applicant): Dry eye, a group of disorders that affects ~5 million people over the age of 50 in the USA today, is characterized by inadequate hydration and lubrication of the ocular surface. The final common pathway for all types of dry eye is disruption of the ocular surface barrier, which can be assessed by quantifying uptake of water-soluble dyes applied topically to the ocular surface. In preliminary data using a preclinical model, it is shown that topical delivery of clusterin (CLU), a natural homeostatic tear protein, prevents and ameliorates barrier disruption in a preclinical model by a remarkable sealing mechanism dependent on attainment of a critical all-or-none threshold. The anti-inflammatory, proteostatic and cytoprotective activities of CLU are well known. It is shown that CLU binds to the ocular surface subjected to desiccating stress selectively and positioned in this way, it also protects barrier structure. The long-term goal of Proteris Biotech, Inc. is to translate CLU to the clinic a an FDA-approved biotherapeutic. This Phase I STTR application has two immediate scientific goals: 1) to establish and perform good manufacturing practices (GMP)-compatible production of a human recombinant form of CLU, called "Protearin", under non-GMP conditions; 2) to demonstrate that Protearin is functionally equivalent to human plasma-derived CLU and compare its efficacy to two reference compounds. In addition, planning activities for STTR Phase II will be performed including, 1) writing a protocol to transfer the process for Protearin production to a GMP lab, and for adapting to GMP compliance; 2) identifying a qualified subcontractor for Good Laboratory (GLP) testing of GMP-produced Protearin; 3) writing a protocol for a "first-in-human" phase I clinical trial of Protearin, the goal to assess product safty and provide proof-of-principal of efficacy in humans; 4) recruiting collaborators/consultants and searching for new lab space for executing these next steps. Most efforts for new drug development in the DE arena have been devoted to targeting of inflammation, tear production, tear film movement and tear chemistry, i.e., factors located upstream in the cascade of events leading to DE and OCS disruption. These factors differ and the various types of dry eye. CLU's action in sealing at the OCS has not been described for any other drug under development. A therapeutic that can target upstream factors in dry eye, as well as barrier disruption, the final common endpoint, represents an important innovation.