Stimulation of Tear Secretion by a Novel Glycoprotein

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.