Stimulation of Tear Secretion by a Novel Glycoprotein

描述(由申请人提供)描述：干眼症是一种普遍存在的眼表疾病，常被忽视、诊断不足且知之甚少。干眼症是一种多因素疾病，具有分泌功能低下、自身免疫、炎症、激素、神经源性和医源性等多种成分。所有病因的共同之处是泪液分泌量和质量的下降。目前还没有被批准的促进泪液分泌的局部药物，可以解决缺水干眼症的主要缺陷。与目前的治疗方法相比，Lacritin是一种稳定的新型人类泪液糖蛋白，基于其抗炎作用和刺激泪液流动的自然能力，具有独特的作用机制。作为泪液的天然成分，催泪素不仅刺激角膜/泪腺轴增加泪液产量，还能促进人类泪液细胞的生长，通过角膜上皮刺激保护性粘蛋白MUC16的表达，与Syndecan-1结合，并具有抗肿瘤坏死因子的细胞保护作用，这表明催泪素可能也具有有益的抗炎作用。第一阶段的主要成果是证明了在细胞培养中观察到的Lacritin的作用可以在体内复制，并可以构成第二阶段拟议的临床前试验的基础。在兔模型上局部应用Lacritin的所有三个第一阶段标准都符合：(1)泪流增加，(2)产生正常成分的泪水，(3)不刺激眼组织。此外，应用拉西汀1个月后，其疗效不随重复使用而减弱，也未出现毒性反应。此外，还构建了一系列活性C-端和N-端缺失结构，可能更适合于药物开发。他们将在第二阶段进行测试。这一转化研究项目的长期目标是开发一种有效的、无毒的局部治疗方法。具体目标包括(1)在局部给药后最大限度地增加泪液产量，并将不良反应降至最低；(2)确定泪液吸收、分布和排泄的基本参数；(3)在适当的载体和容器中实现生产的经济性、稳定性和最佳保质期；(4)为GLP生产足够的泪液，以进行临床前试验。此外，抗炎作用的证据也将被记录在案。第二阶段的目标是确定Lacritin结构并进行临床前试验以支持IND提交。如果成功，催泪素将成为第一个通过增加泪液产量、减少炎症和修复受损泪液组织来对抗干眼症的药物。干眼是一种普遍存在的、诊断不足且知之甚少的眼表疾病，影响着2500多万美国人的生活质量，特别是妇女和老年人口。所有病因的共同之处是泪液分泌量和质量的下降，但目前还没有批准的外用药物来增强泪液的产生。我们的目的是配制一种局部滴眼液，既能刺激泪液的生理性分泌，又能控制潜在的炎症。

DESCRIPTION (provided by applicant): Description Dry eye is a ubiquitous, often overlooked, under diagnosed and poorly understood affliction of the ocular surface. As a multifactorial disease, dry eye has hyposecretory, auto-immune, inflammatory, hormonal, neurogenic, and iatrogenic components. Common to all etiologies is a decrease of both volume and quality of tear secretion. There are currently no approved topical agents for enhancement of tear secretion, which would address the primary defect in aqueous deficiency dry eye disease. Compared to current therapy, lacritin, a stable, novel human tear glycoprotein, has a unique mechanism of action based upon its anti-inflammatory effects and natural ability to stimulate tear flow. A natural component of tears, lacritin not only stimulates the cornea/lacrimal gland axis to increase tear production, but also promotes the growth of human lacrimal cells, stimulates expression of MUC16, a protective mucin, by corneal epithelium, binds to syndecan-1 and is cytoprotective against TNF, which suggest that lacritin may also have beneficial anti-inflammatory effects. The major achievement of Phase I was demonstrating that the effects of lacritin observed in cell culture can be replicated in vivo and can form the basis for the preclinical trials proposed for Phase II. All 3 Phase I criteria were met as topical application of lacritin in a rabbit model (1) increased tear flow, (2) produced tears of normal composition and (3) did not irritate ocular tissues. In addition, application of lacritin for 1 month showed that the response does not diminish with repeated application, nor do toxic effects appear. Also, a series of active C-terminal and N-terminal deletion constructs of lacritin were created, which may be more suitable for drug development. They will be tested in Phase II. Long-term goals of this translational research project are to develop an active lacritin construct as an efficacious, nontoxic topical treatment. Specific aims include (1) Optimal increased tear production with minimal adverse reactions after topical administration in an in vivo rabbit dry eye model, (2) Determination of basic parameters of lacritin absorption, distribution, and excretion, (3) Economy of manufacture, stability and optimal shelf life in an appropriate vehicle and container, (4) Scale up for GLP manufacture of sufficient lacritin to conduct preclinical trials. Moreover, evidence of anti-inflammatory effects will also be documented. The goal for Phase II is to identify lacritin constructs and perform preclinical trials to support IND submission. If successful, lacritin would be the first agent to combat dry eye by increasing tear production, reducing inflammation and restoring damaged lacrimal tissue. Dry eye is a ubiquitous, under diagnosed and poorly understood ocular surface disease that affects the quality of life of over 25 million Americans, especially women and the geriatric population. Common to all etiologies is a decrease in both volume and quality of tear secretion, but there are no approved topical agents that enhance tear production. Our intent is to formulate a lacritin construct as a topical eye drop that will both stimulate physiologic lacrimal tear secretion and control the underlying inflammation.