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，诊断不足和了解不多的眼表疾病。作为一种多因素疾病，干眼症具有分泌不足、自身免疫、炎症、激素、神经源性和医源性成分。所有病因的共同点是泪液分泌量和质量的降低。目前还没有批准的用于增强泪液分泌的外用药物，这将解决房水缺乏性干眼病的主要缺陷。与目前的治疗相比，催泪素是一种稳定的新型人泪液糖蛋白，具有独特的作用机制，基于其抗炎作用和刺激泪液流动的天然能力。作为泪液的天然成分，催泪素不仅刺激角膜/泪腺轴以增加泪液产生，而且还促进人泪腺细胞的生长，刺激角膜上皮表达MUC 16（一种保护性粘蛋白），与多配体蛋白聚糖-1结合，并且对TNF具有细胞保护作用，这表明催泪素也可能具有有益的抗炎作用。I期的主要成就是证明了在细胞培养中观察到的催乳素的作用可以在体内复制，并且可以形成II期临床前试验的基础。在兔模型中局部应用催泪素，满足所有3项I期标准（1）增加泪液流量，（2）产生正常组成的泪液，（3）不刺激眼组织。此外，应用催乳素1个月表明，重复应用不会降低反应，也不会出现毒性作用。此外，一系列的活性的C-末端和N-末端缺失构建体的lacritin，这可能是更适合于药物开发。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活性lacritin结构作为一种有效的，无毒的局部治疗。具体目标包括：（1）在兔干眼体内模型中局部给药后，泪液产量最佳增加，不良反应最小，（2）确定催泪素吸收、分布和排泄的基本参数，（3）适当溶媒和容器中的生产经济性、稳定性和最佳有效期，（4）按GLP规模生产足够的催泪素，以进行临床前试验。此外，还将记录抗炎作用的证据。II期的目标是鉴定lacritin结构并进行临床前试验以支持IND提交。如果成功的话，催泪素将是第一种通过增加泪液分泌、减少炎症和修复受损的泪液组织来治疗干眼症的药物。干眼症是一种普遍存在的、诊断不足且知之甚少的眼表疾病，其影响超过2500万美国人的生活质量，尤其是女性和老年人群。所有病因的共同点是泪液分泌量和质量的降低，但没有批准的局部药物可以增强泪液的产生。我们的目的是将催泪蛋白构建体配制成局部滴眼液，其既刺激生理性泪液分泌又控制潜在炎症。

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.