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Protection and Treatment of the Ocular Surface Barrier

眼表屏障的保护和治疗

基本信息

批准号：
9334035
负责人：
M. Elizabeth Fini
金额：
$ 8万
依托单位：
PROTERIS BIOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334035
关键词：
Adverse effects Affect Age Anti-Inflammatory Agents Anti-inflammatory Apoptosis Artificial Tears Autoimmune Process Basic Science Binding Biochemical Biological Biological Assay Biological Products Biological Response Modifier Therapy Biotechnology Blindness California Cells Chemistry Cities Clinic Clinical Trials Core Facility Cyclosporine Data Development Disease Dose Drops Dyes Etiology Event Failure Film Fluorescence Resonance Energy Transfer Formulation Galactose Binding Lectin Galectin 3 Goals Health Personnel Human Hydration status In Vitro Inflammation Inflammatory Investigation Laboratories Lead Licensing Liquid substance Lubrication MMP9 gene Mammalian Cell Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Molecular Chaperones Movement Mus Operative Surgical Procedures Outcome Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Phase Phase I Clinical Trials Plasma Population Positioning Attribute Pre-Clinical Model Process Production Property Proteins Protocols documentation Publications Recombinants Recruitment Activity Reporting Research Safety Small Business Technology Transfer Research Stress Structure Testing Therapeutic Time Tissues Topical application Translating Vision Water Woman Work Writing base cost effective drug development evaporation expression vector eye dryness good laboratory practice in vivo innovation large scale production manufacturing process mouse model mutant novel novel therapeutics ocular surface pre-clinical prevent process optimization programs public health relevance seal small molecule sulfated glycoprotein 2 synthetic peptide tear proteins uptake

项目摘要

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.

描述（由申请人提供）：干眼是一组影响当今美国约500万50岁以上人群的疾病，其特征在于眼表水合和润滑不足。所有类型干眼的最终共同途径是眼表屏障的破坏，这可以通过定量局部应用于眼表的水溶性染料的摄取来评估。在使用临床前模型的初步数据中，显示局部递送丛生蛋白（CLU）（一种天然稳态泪液蛋白）通过依赖于达到关键的全或无阈值的显著密封机制来预防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活性是众所周知的。结果表明，CLU选择性地结合于受干燥应激的眼表，并以这种方式定位，它也保护屏障结构。Proteris Biotech，Inc.的长期目标将CLU转化为FDA批准的生物制剂。该I期STTR申请具有两个直接的科学目标：1）在非GMP条件下建立并执行良好生产规范（GMP）相容的CLU的人重组形式（称为“Protearin”）的生产; 2）证明Protearin在功能上等同于人血浆来源的CLU，并将其功效与两种参比化合物进行比较。此外，将进行STTR第II阶段的规划活动，包括：1）编写方案，将蛋白质生产工艺转移到GMP实验室，并适应GMP合规性; 2）确定合格的分包商，对GMP生产的蛋白质进行药物非临床研究质量管理规范（GLP）检测; 3）编写Protearin的“首次人体”I期临床试验方案，目的是评估产品安全性并提供人体有效性的主要证据; 4）招募合作者/顾问，并寻找新的实验室空间来执行这些后续步骤。DE竞技场中新药开发的大部分努力致力于靶向炎症、泪液产生、泪膜运动和泪液化学，即，位于事件级联上游的因素导致DE和OCS中断。这些因素不同，干眼症的各种类型。CLU在OCS的密封作用尚未描述用于任何其他正在开发的药物。一种可以靶向干眼上游因素以及屏障破坏（最终的共同终点）的治疗方法代表了一项重要的创新。