The Development Epithelial Sodium Channel Blockers for Chronic Dry Eye

描述（由申请人提供）：干眼症是最常见的眼部疾病之一，仅在美国就有超过500万人受到影响。干眼症是一种多因素疾病，常见的病因是泪膜不足导致眼表损伤和眼部不适。目前可用的几种治疗方法，包括免疫抑制剂和非处方泪液替代品，对许多使用者来说不够有效，或者只能暂时缓解干眼症状。因此，开发治疗干眼症的新型药物将对治疗环境产生巨大的好处。眼表泪液膜的体积代表泪液输出与泪液通过引流、蒸发或上皮吸收损失之间的平衡。与其他上皮组织类似，结膜和角膜上皮能够通过活性盐和水的运输调节粘膜表面的水化状态。上皮钠通道（ENaC）是包括眼睛在内的许多组织中钠（和水）吸收的关键调节器。预计ENaC在眼内的抑制作用可保护泪液分泌物并维持眼表水合作用。Parion Sciences已经开发了一系列新的化合物，可以特异性和有效地抑制ENaC，预计这些化合物将成为临床开发治疗干眼症的良好候选分子。在概念验证研究中，Parion化合物在正常小鼠和大鼠中产生浓度依赖性的泪液输出增加，持续时间超过8小时。此外，Parion化合物显著增加泪液输出，并与干眼小鼠模型中改善的角膜染色有关。综上所述，这些数据表明Parion化合物是临床开发的优秀候选者。在临床项目开始之前，必须选择导联分子并在人体模型系统中进行验证。Parion公司的ENaC阻滞剂文库包含500种新化合物，确定一种作用时间最长的候选药物对Parion公司干眼症项目的成功至关重要。在本提案中，我们概述了一系列研究，这些研究将帮助Parion选择最有希望的先导化合物，以推进临床开发。

DESCRIPTION (provided by applicant): Dry eye is one of the most frequently diagnosed ocular diseases affecting more than 5 million people in the United States alone. Dry eye is s a multi-factorial disease, resulting from a common etiology of insufficient tear film causing ocular surface damage and symptoms of ocular discomfort. The few current therapies available, which include immunosuppressive agents and over-the-counter tear replacements, are not sufficiently efficacious for many users or only provide transient relief from dry eye symptoms. Therefore, the development of novel agents to treat dry eye would be of tremendous benefit to the therapeutic milieu. The volume of tear film on the ocular surface represents a balance between tear fluid output versus fluid loss via drainage, evaporation, or epithelial absorption. Similar to other epithelial tissues, the epithelium of the conjunctiva and cornea are capable of regulating the hydration status of the mucosal surface through active salt and water transport. The epithelial sodium channel (ENaC) is a key regulator of sodium (and water) absorption in numerous tissues including the eye. The inhibition of ENaC in the eye is predicted to preserve lacrimal secretions and maintain hydration on the ocular surface. Parion Sciences has developed a novel series of compounds that specifically and potently inhibit ENaC, which are predicted to be good candidate molecules for clinical development for the treatment of dry eye. In proof-of-concept studies, Parion compounds produce a concentration-dependent increase in tear output that persists for greater than 8 hours in normal mice and rats. Furthermore, Parion compounds significantly increase tear output and are associated with improved corneal staining in a dry eye mouse model. Taken together, these data suggest that the Parion compounds are excellent candidates for clinical development. Prior to the initiation of a clinical program it is essential that a lead molecule be chosen and validated in a human model system. Parion's ENaC blocker library contains >500 novel compounds and identifying a lead candidate with the longest duration of action is critical to the success of Parion's dry eye program. In this proposal we outline a series of studies that will assist Parion in the selection of the most promising lead compounds to advance towards clinical development. PUBLIC HEALTH RELEVANCE: Keratoconjunctivitis sicca (KCS) or chronic dry eye disease (DED) is one of the most frequently diagnosed ocular diseases, resulting in painful irritation of the eye and impaired vision. KCS/DED often results from inadequate aqueous tear fluid on the eyes. Parion Sciences is developing a novel therapeutic agent that is predicted to provide long acting relief from dry eye symptoms.