SBIR-STTR Award

Dry eye is a ubiquitous, often overlooked, underdiagnosed and poorly understood affliction of the ocular surface. This common opthalmological complaint can markedly affect a patient's quality of life. As a multifactorial disease, dry eye has hyposecretory, auto-immune, inflammatory, hormonal, neurogenic, toxic, and iatrogenic components. Common to all etiologies is a decrease in both volume and quality of tear secretion. Current therapy ranges from topical application of aqueous, oil and gel tear film constituent replacement "artificial" tears, to topical anti-inflammatory drugs, to oral secretagogues. There are currently no approved topical agents indicated for enhancement of tear flow and production, which would address the primary defect in aqueous deficiency dry eye disease. Lacritin is a stable, novel human tear glycoprotein produced solely by lacrimal and salivary glands. It binds to and stimulates a rapid, sustained release of calcium in cultured corneal epithelial cells, which suggests topical application of lacritin may stimulate the cornea/lacrimal gland axis to increase tear production. Based upon these properties elucidated in cell culture, we hypothesize that lacritin has potential as a therapeutic agent to promote tear production. Compared to current therapy, as an ocular-specific prosecretory glycoprotein, lacritin has a unique mechanism of action. We expect that topical application of lacritin will increase tear production by stimulation of the lacrimal gland/corneal axis. The long-term goals of this translational research project are to develop lacritin as an efficacious, nontoxic topical treatment. Specific aims for this proposal are (1) demonstration, using an in vivo rabbit model, of the ability of lacritin to increase tear production after topical administration, (2) determination of the effect of lacritin on the normal composition of tears, and (3) examination of lacritin-treated ocular tissues for signs of adverse effects. The primary outcome measurement is lacritin's ability to increase tear production. In vivo analysis also includes confocal microscopy, slit lamp biomicroscopy, digital photography, application of the MacDonald-Shadduck Scale for Ocular Toxicity, tear break up time, vital dye assessment with fluorescein and Lissamine green, and Schirmer's test for tear production.

Thesaurus Terms:
biotherapeutic agent, drug design /synthesis /production, drug screening /evaluation, eye pharmacology, glycoprotein, keratoconjunctivitis sicca, secretion, tear biological model, calcium flux, cell proliferation, corneal epithelium, eye disorder chemotherapy, fluid flow, lacrimal apparatus, nonhuman therapy evaluation, pharmacokinetics, protein binding, salivary gland, topical drug application laboratory rabbit

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.

Project Terms:
1,2,3-Propanetriol; 1,2,3-Trihydroxypropane; Absorption; Achievement; Achievement Attainment; Acinar Cell; Aciner Cells; Address; Adverse reactions; Affect; Aged 65 and Over; Aging; Allergy; American; Androgenic Agents; Androgenic Compounds; Androgens; Animal Model; Animal Models and Related Studies; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Apoptosis; Apoptosis Pathway; Autoimmune Diseases; Award; Binding; Binding (Molecular Function); Biological Models; Blepharospasm; Blindness; Blood Coagulation Factor IV; Body Tissues; C-terminal; Ca++ element; Calcium; Causality; Cell Death, Programmed; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell membrane; Cells; Cellular Proliferation; Cellulose, methyl ether; Charge; Cicatrix; Citrucel; Coagulation Factor IV; Common Rat Strains; Complex; Computers; Contact Lenses; Cornea; Cultured Cells; Cyclic GMP; Cyclosporines; Cyclosporins; Cytoplasmic Membrane; DIF; DNA Molecular Biology; Defect; Diagnosis; Disease; Disorder; Dose; Drug Administration, Topical; Drug Therapy; Drugs; Dryness of eye; Duct; Duct (organ) structure; Ductal Cell; Ductal Epithelial Cell; Dysfunction; Elderly; Elderly, over 65; Electrolytes; Emollients; Epithelium, Anterior Corneal; Epithelium, Corneal; Esthesia; Etiology; Excretory function; Eye; Eye Burns; Eye Drops; Eye diseases; Eyeball; Eyedrops; Factor IV; Feeling; Foreign Bodies; Functional disorder; GFAC; Generalized Growth; Glaucoma; Glycerin; Glycerol; Glycoproteins; Goals; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Guanosine Cyclic 3',5'-Monophosphate; Guanosine Cyclic Monophosphate; Guanosine, cyclic 3',5'-(hydrogen phosphate); Head and Neck, Salivary Glands; Hormonal; Human; Human, General; Hypersensitivity; INFLM; Immune; In Vitro; Infection; Inferior; Inflammation; Inflammatory; Journals; Keratitis; Keratomileusis, Laser In Situ; Keratopathy; LASIK; Lacrimal Glands; Lacrimal gland structure; Laser In Situ Keratomileusis; Laser Intrastromal Keratomileuses; Laser Intrastromal Keratomileusis; Laser-Assisted Stromal In Situ Keratomileusis; Life; Light Sensitivity; Magazine; Mammals, Rabbits; Mammals, Rats; Man (Taxonomy); Man, Modern; Medication; Meniscus; Meniscus structure of joint; Methyl Cellulose; Methylcellulose; Model System; Modeling; Models, Biologic; Molecular Biology; Molecular Interaction; Mucins; Mucous body substance; Mucus; Mucus Glycoprotein; N-terminal; NH2-terminal; Operation; Operative Procedures; Operative Surgical Procedures; Oryctolagus cuniculus; Pain; Painful; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Photophobia; Physiologic; Physiological; Physiology; Physiopathology; Plasma Membrane; Population; Process; Process of absorption; Production; Property; Property, LOINC Axis 2; Proteins; Protocol; Protocols documentation; QOL; Quality of life; R01 Mechanism; R01 Program; RPG; Rabbit, Domestic; Rabbits; Rat; Rattus; Reading; Redness; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; STTR; Saline; Saline Solution; Salivary Glands; Scars; Secretory Granules; Secretory Vesicles; Senescence; Sensation; Series; Sjogren's Syndrome; Sjogrens; Small Business Technology Transfer Research; Solutions; Steroid Compound; Steroids; Structure of corneal epithelium; Surface; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; TNF; TNF A; TNF gene; TNFSF2; Testing; Therapeutic; Therapeutic Agents; Therapeutic Androgen; Time; Tissue Growth; Tissues; Topical agent; Topical application; Toxic effect; Toxicities; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; Translational Research; Translational Research Enterprise; Translational Science; Trauma; Tumor Necrosis Factor Gene; Tyrosine Phosphorylation; Woman; advanced age; aqueous; autoimmune disorder; base; cGMP; combat; commercial application; corneal; corneal allograft; corneal epithelial; corneal epithelium; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; drug development; drug/agent; dry eye; elders; excretion; eye disorder; eye dryness; feelings; gene discovery; gene product; geriatric; glaucomatous; guanosine 3'5' monophosphate; impression; in vivo; innovate; innovation; innovative; irritation; lacrimal; late life; later life; manufacturing scale-up; meetings; model organism; mucous; new therapeutics; next generation therapeutics; novel; novel therapeutics; ocular surface; older adult; older person; ontogeny; ophthalmopathy; palliative; pathophysiology; plasmalemma; preclinical study; response; scale up; senescent; senior citizen; surgery; syndecan; tear proteins; topical administration; topical drug application; topically applied; translation research enterprise