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（由适用提供）：干眼症，这是一组影响当今美国50岁以上约500万人的疾病，其特征是眼表面的水合不足和润滑不足。所有类型的干眼症的最终公共途径是破坏眼表屏障，可以通过量化局部应用于眼表面的水溶性染料的摄取来评估。在使用临床前的初步数据中，表明簇蛋白（CLU）的局部递送（一种天然的稳态撕裂蛋白）通过依赖于达到关键的全或任何人阈值的显着密封机制来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活性是众所周知的。结果表明，CLU与受到干燥应力有选择性并以这种方式定位的眼表结合，也可以保护屏障结构。 Proteris Biotech，Inc。的长期目标是将CLU转换为FDA批准的生物疗法。此I阶段的STTR应用具有两个直接的科学目标：1）在非GMP条件下，建立和执行良好的制造实践（GMP）兼容人类重组形式的CLU，称为“ Protearin”； 2）证明蛋白质在功能上等同于人血浆衍生的CLU，并将其有效性与两种参考化合物进行比较。此外，将进行STTR II期的计划活动，包括：1）编写一项协议，将protearin生产过程转移到GMP实验室，并适应GMP合规性； 2）确定GMP生产的蛋白质的良好实验室（GLP）测试的合格分包商； 3）编写针对Protearin的I期临床试验的“第一阶段”临床试验的方案，该试验的目标是评估产品安全性并提供人类效率的原理证明； 4）招募合作者/顾问，并寻找新的实验室空间来执行这些下一步。 DE竞技场新药开发的大多数努力都致力于靶向感染，泪液产生，泪液膜运动和撕裂化学的靶向，即位于导致DE和OCS破坏的事件上游的因素。这些因素有所不同，干眼各种类型。 CLU在OCS上密封的行动尚未针对正在开发的任何其他药物进行描述。一种可以针对干眼症上游因素以及屏障破坏（最终共同终点）的疗法代表了重要的创新。