Stimulation of Tear Secretion by a Novel Glycoprotein

新型糖蛋白刺激泪液分泌

• 批准号: 7225330
• 负责人: JOHN D SHEPPARD
• 金额: $ 31.92万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225330
• 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; Blur; C-terminal; Calcium; Cell Proliferation; Cell membrane; Cells; Charge; Cicatrix; Complex; Computers; Contact Lenses; Cornea; Cultured Cells; 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; Range; 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; commercial application; corneal allograft; corneal epithelium; drug development; eye dryness; gene discovery; impression; in vivo; innovation; irritation; lacrimal; novel; novel therapeutics; ocular surface; 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）：描述干眼症是无处不在的，经常被忽略的，在被诊断出且对眼表面的痛苦不足。作为一种多因素疾病，干眼症患有偏射，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的体积和质量均降低。目前尚无批准的局部药物来增强泪液分泌，这将解决水缺乏干眼症的主要缺陷。与当前的疗法相比，基于其抗炎作用和刺激泪液流动的自然能力，稳定的新型人撕裂糖蛋白是一种稳定的新型人撕裂糖蛋白。泪素的自然成分，不仅刺激角膜/泪腺轴增加泪液产生，还促进了人类泪细胞的生长，刺激了通过角膜上皮的Muc16的表达，一种保护性粘蛋白，与角膜上皮相结合，与Syndecan-1和Syndecan-1和Syndecan-1和Syndecan-1和Syndecan-1和对TNF具有细胞保护作用，这表明酸性蛋白也可能具有有益的抗炎作用。第一阶段的主要成就表明，在细胞培养中观察到的透眼素的作用可以在体内复制，并可以为提出的II期临床前试验构成基础。所有3期I标准均作为兔模型中的局部应用（1）撕裂流动增加，（2）产生正常组成的撕裂，（3）不会刺激眼组织。此外，施用卓蛋白1个月表明，反复应用的反应不会减少，也不会出现有毒作用。同样，创建了一系列活跃的C末端和N末端缺失构建体，这可能更适合药物开发。它们将在第二阶段进行测试。这项转化研究项目的长期目标是开发一种活跃的长丁蛋白构建体，作为一种有效的，无毒的局部处理。具体目的包括（1）在体内兔干眼模型中局部给药后最小的不良反应增加泪液产生，（2）确定基本吸收，分布和排泄的基本参数，（3）制造的经济，稳定性，稳定性，稳定性以及适当的车辆和容器中的最佳保质期，（4）扩大规模，以使GLP生产足够的透眼素以进行临床前试验。此外，还将记录具有抗炎作用的证据。第二阶段的目标是识别流质蛋白构建体并执行临床前试验以支持IND提交。如果成功的话，长丁蛋白将是第一种通过增加泪液产生，减少炎症和恢复受损的泪液组织来对抗干眼眼症的药物。干眼症是一种普遍存在的，在被诊断出且知情的眼表疾病不足，影响了超过2500万美国人，尤其是妇女和老年人群的生活质量。所有病因的共同点是泪液分泌的体积和质量都降低，但是没有批准的局部用药可以增强撕裂的产生。我们的目的是制定植物素构建体作为局部眼部滴，既可以刺激泪液泪液的分泌，又可以控制潜在的炎症。