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、经常被忽视的、未被诊断和知之甚少的眼表疾患。作为一种多因素疾病，干眼症具有低分泌、自身免疫、炎症、激素、神经源性和医源性成分。所有病因的共同特点是泪液分泌量和质量的降低。目前还没有被批准用于增强泪液分泌的外用药物，这将解决水缺乏性干眼病的主要缺陷。与目前的治疗方法相比，泪素是一种稳定的新型人泪液糖蛋白，基于其抗炎作用和天然刺激泪液流动的能力，具有独特的作用机制。泪素是眼泪的天然成分，它不仅刺激角膜/泪腺轴增加眼泪的产生，还促进人类泪细胞的生长，刺激角膜上皮保护性粘蛋白MUC16的表达，与syndecan-1结合，对TNF具有细胞保护作用，这表明泪素也可能具有有益的抗炎作用。第一阶段的主要成就是证明了在细胞培养中观察到的催泪素的作用可以在体内复制，并且可以形成第二阶段临床前试验的基础。在兔模型中局部应用泪素满足所有3个I期标准：(1)增加泪液流量，(2)产生正常成分的泪液，(3)不刺激眼部组织。此外，应用1个月的催泪素显示，反应不减少反复应用，也没有出现毒性作用。此外，我们还构建了一系列活性的c端和n端缺失构建体，这些构建体可能更适合于药物开发。它们将在第二阶段进行测试。这个转化研究项目的长期目标是开发一种有效的、无毒的局部治疗的活性催泪素结构。具体目标包括(1)在兔体内干眼模型中局部给药后，以最小的不良反应优化泪液产量；(2)确定泪液素吸收、分布和排泄的基本参数；(3)在合适的载体和容器中生产的经济性、稳定性和最佳保质期；(4)扩大生产足够的泪液素的GLP生产规模，进行临床前试验。此外，抗炎作用的证据也将被记录下来。II期的目标是确定泌乳素结构并进行临床前试验，以支持IND申请。如果成功，泪素将成为第一种通过增加泪液分泌、减少炎症和修复受损泪液组织来对抗干眼症的药物。干眼症是一种普遍存在的、诊断不清、对眼表疾病知之甚少的疾病，它影响着2500多万美国人的生活质量，尤其是女性和老年人。所有病因的共同特点是泪液分泌量和质量的下降，但目前还没有批准的局部药物可以增强泪液分泌。我们的目的是研制一种泪素结构，作为局部滴眼液，既能刺激生理性泪液分泌，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.