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科疾病之一，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，由泪膜不足的常见病因引起，导致眼表损伤和眼部不适症状。目前可用的几种疗法，包括免疫抑制剂和非处方泪液替代物，对许多使用者来说不够有效，或者仅提供干眼症状的短暂缓解。因此，开发治疗干眼症的新型药物将对治疗环境产生巨大益处。眼表上的泪膜体积代表泪液输出与经由引流、蒸发或上皮吸收的流体损失之间的平衡。与其他上皮组织类似，结膜和角膜的上皮能够通过主动盐和水转运来调节粘膜表面的水合状态。上皮钠通道（ENaC）是包括眼睛在内的许多组织中钠（和水）吸收的关键调节剂。预测眼内ENaC的抑制可保存泪液分泌物并维持眼表面的水合作用。Parion Sciences开发了一系列特异性和有效抑制ENaC的新型化合物，预计这些化合物将成为治疗干眼症的临床开发的良好候选分子。在一系列临床前研究中，Parion选择了一种先导化合物（P-301）作为新的干眼症治疗药物。在干眼症动物模型中，P-301显著增加泪液分泌，作用持续时间长（>4小时），并治疗与干眼症相关的角膜表面损伤。在初步的非临床安全性研究中，P-301在高浓度下耐受性良好。此外，P- 301是眼用制剂的理想候选物，因为它在溶液中高度可溶且稳定。Parion正在继续在IND使能研究中开发P-301，以进行人体临床试验。 公共卫生相关性：干燥性角结膜炎（KCS）或慢性干眼病（DED）是最常诊断的眼部疾病之一，导致疼痛刺激、眼表炎症和视力受损。KCS/DED由眼睛上的含水泪液不足引起。Parion Sciences正在开发一种新型治疗剂，预计可长期缓解干眼症症状。

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 a series of pre-clinical studies, Parion has selected a lead compound (P-301) for development as a new therapeutic agent for dry eye. In dry eye animal models, P-301 significantly increases tear output with a long (>4 hour duration of action) and treats the corneal surface damage associated with dry eye. In preliminary non-clinical safety studies, P-301 has been well tolerated at high concentrations. Additionally, P- 301 is an ideal candidate for ophthalmic formulations as it is highly soluble and stable in solution. Parion is continuing the development of P-301 in IND-enabling studies towards clinical testing in man. 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, inflammation on the ocular surface, and impaired vision. KCS/DED 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.