Stimulation of Tear Secretion by a Novel Glycoprotein

新型糖蛋白刺激泪液分泌

• 批准号: 7849336
• 负责人: JOHN D SHEPPARD
• 金额: $ 2.55万
• 依托单位: EYERX RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849336
• 关键词: Achievement; Acinar Cell; Address; Adverse reactions; Affect; Aging; American; Androgens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autoimmune Diseases; Award; Binding; Biological Models; Blepharospasm; Blindness; C-terminal; Calcium; Cell Culture Techniques; Cell Proliferation; Cell membrane; Cells; Charge; Cicatrix; Complex; Computers; Contact Lenses; Cornea; Cyclic GMP; Cyclosporins; Defect; Diagnosis; Disease; Dose; Duct (organ) structure; Ductal Epithelial Cell; Elderly; Electrolytes; Emollients; Esthesia; Etiology; Excretory function; Eye; Eye Burns; Eye diseases; Eyedrops; Feeling; Foreign Bodies; Functional disorder; Glaucoma; Glycerol; Glycoproteins; Goals; Growth; Growth Factor; Hormonal; Human; Hypersensitivity; Immune; In Vitro; Infection; Inferior; Inflammation; Inflammatory; Journals; Keratitis; Keratopathy; Lacrimal gland structure; Laser In Situ Keratomileusis; Life; Meniscus structure of joint; Methylcellulose; Modeling; Molecular Biology; Mucins; Mucous body substance; N-terminal; Operative Surgical Procedures; Oryctolagus cuniculus; Pain; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Photophobia; Physiological; Physiology; Population; Process; Production; Property; Proteins; Protocols documentation; Quality of life; Rattus; Reading; Redness; Research Project Grants; Saline; Salivary Glands; Secretory Vesicles; Series; Sjogren' s Syndrome; Small Business Technology Transfer Research; Solutions; Steroids; Surface; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Topical agent; Topical application; Toxic effect; Transcriptional Regulation; Translational Research; Trauma; Tyrosine Phosphorylation; Woman; absorption; aqueous; base; combat; commercial application; corneal allograft; corneal epithelium; drug development; eye dryness; gene discovery; impression; in vivo; innovation; irritation; lacrimal; manufacturing scale-up; meetings; novel; novel therapeutics; ocular surface; palliative; preclinical study; response; scale up; syndecan; tear proteins

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.

描述（由申请人提供）： 描述 干眼症是一种普遍存在、经常被忽视、诊断不足且了解甚少的眼表疾病。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下降。目前还没有批准的局部药物可以增强泪液分泌，从而解决水液缺乏性干眼病的主要缺陷。与目前的疗法相比，泪泌素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天然能力，具有独特的作用机制。泪液的天然成分，泪液素不仅能刺激角膜/泪腺轴增加泪液的产生，还能促进人类泪液细胞的生长，刺激角膜上皮表达保护性粘蛋白MUC16，与syndecan-1结合，对 TNF 具有细胞保护作用，这表明乳泌素还可能具有有益的抗炎作用。第一阶段的主要成就是证明在细胞培养中观察到的乳泌素的作用可以在体内复制，并且可以为第二阶段提出的临床前试验奠定基础。所有 3 个 I 期标准均满足，因为在兔模型中局部应用乳泌素 (1) 增加泪液流量，(2) 产生正常成分的眼泪，(3) 不刺激眼组织。另外，应用lacritin 1个月表明，效果并不因重复应用而减弱，也未出现毒性作用。此外，还创建了一系列活性的lacritin C端和N端缺失构建体，这可能更适合药物开发。它们将在第二阶段进行测试。该转化研究项目的长期目标是开发一种活性催乳素结构，作为一种有效、无毒的局部治疗方法。具体目标包括 (1) 在兔体内干眼模型中局部给药后，以最佳方式增加泪液产生，同时将不良反应降至最低，(2) 确定泪泌素吸收、分布和排泄的基本参数，(3) 制造经济性、稳定性以及在适当的载体和容器中的最佳保质期，(4) 扩大 GLP 生产充足的乳泌素以进行临床前试验。此外，还将记录抗炎作用的证据。第二阶段的目标是确定乳泌素结构并进行临床前试验以支持 IND 提交。如果成功，泪泌素将成为第一个通过增加泪液产生、减少炎症和恢复受损泪腺组织来对抗干眼症的药物。干眼症是一种普遍存在、诊断不足且了解甚少的眼表疾病，影响着超过 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均下降，但尚无批准的局部药物可增强泪液产生。我们的目的是配制一种泪泌素结构作为局部滴眼剂，既能刺激生理性泪液分泌，又能控制潜在的炎症。