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。在一系列的临床前研究中，Parion公司选择了一种先导化合物（P-301）作为干眼症的新型治疗剂进行开发。在干眼动物模型中，P-301显著增加泪液输出，且持续时间长（约4小时），治疗干眼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是眼科配方的理想候选物，因为它在溶液中高度可溶且稳定。Parion正在继续开发P-301，使其能够在人体中进行临床试验。

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.