The Development Epithelial Sodium Channel Blockers for Chronic Dry Eye

描述(申请人提供)：干眼症是最常见的眼科疾病之一，仅在美国就有500多万人受到影响。干眼症是S的一种多因素疾病，由泪膜不足引起的眼表损伤和眼部不适症状是常见的病因。目前可用的为数不多的治疗方法，包括免疫抑制剂和非处方泪液替代品，对许多用户来说并不够有效，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。眼表面泪膜的体积代表泪液输出与通过引流、蒸发或上皮吸收而丢失的泪液之间的平衡。与其他上皮组织相似，结膜和角膜上皮能够通过活跃的盐分和水的运输来调节粘膜表面的水合状态。上皮性钠通道(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。据预测，ENaC在眼睛中的抑制作用可以保护泪液分泌，并保持眼表面的水合。巴黎科学公司已经开发出一系列新的化合物，这些化合物可以特异而有效地抑制ENaC，预计这些化合物将成为治疗干眼的临床开发的良好候选分子。在概念验证研究中，Parion化合物产生浓度依赖的泪液产量增加，在正常小鼠和大鼠身上持续8小时以上。此外，在干眼小鼠模型中，Parion化合物显著增加泪液产量，并与改善角膜染色有关。综上所述，这些数据表明，Parion化合物是临床开发的极佳候选药物。在临床计划开始之前，在人体模型系统中选择和验证一个先导分子是至关重要的。Parion的ENaC阻滞剂库包含500种新化合物，确定作用持续时间最长的主要候选药物对Parion干眼计划的成功至关重要。在这项提案中，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。 公共卫生相关性： 干燥性角结膜炎(KCS)或慢性干眼病(DED)是最常见的眼科疾病之一，导致眼睛疼痛刺激和视力下降。KCS/DED通常是由于眼部含水泪液不足所致。巴黎科学公司正在开发一种新的治疗剂，预计将提供长效缓解干眼症状。

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.