Therapeutic compositions for the treatment of dry eye disease

Abstract

Described herein are materials and methods for treating dry eye disease in a subject.

What is claimed is: 
     
         1 . A method of treating dry eye disease (DED) in a human comprising:
 administering a composition comprising at least one anti-lymphangiogenic agent and a pharmaceutically acceptable carrier to the eye of the human, in an amount effective to treat dry eye disease.   
     
     
         2 . The method of  claim 1 , wherein said anti-lymphangiogenic agent is an inhibitor of VEGF-C- or VEGF-D-mediated signal transduction by VEGFR-2 or VEGFR-3. 
     
     
         3 . The method of  claim 1 , wherein the DED is an autoimmune DED or a DED associated with Sjogren's syndrome. 
     
     
         4 . The method of  claim 1 , wherein the DED is DED due to excessively fast tear evaporation (evaporative dry eyes) or inadequate tear production. 
     
     
         5 . The method of  claim 1 , wherein the dry eye disease is attributable to one or more causes selected from: aging, contact lens usage, medication usage,. 
     
     
         6 . The method of  claim 1 , wherein the dry eye disease is a complication of LASIK refractive surgery. 
     
     
         7 . The method of  claim 1 , wherein the anti-lymphangiogenic agent is purified or isolated. 
     
     
         8 . The method of  claim 1 , wherein said anti-lymphangiogenic agent is selected from the group consisting of: a nucleic acid molecule, an aptamer, an antisense molecule, an RNAi molecule, a protein, a peptide, a cyclic peptide, an antibody or antibody fragment, a polysaccharide, or a small molecule. 
     
     
         9 . The method of  claim 1 , wherein said anti-lymphangiogenic agent is selected from the group consisting of a VEGFR-3 inhibitor, a VEGF-D inhibitor and a VEGF-C inhibitor. 
     
     
         10 . The method of  claim 9 , wherein the anti-lymphangiogenic agent is selected from the group consisting of a VEGF-C antibody, a VEGF-D antibody, a VEGF-R3 antibody, and a polypeptide comprising a soluble VEGFR-3 fragment that binds VEGF-C or VEGF-D. 
     
     
         11 . The method of  claim 10 , wherein the anti-lymphangiogenic agent is a VEGF-C antibody. 
     
     
         12 . The method of  claim 11 , wherein the antibody comprises a heavy chain variable region set forth in amino acids 1-118 of SEQ ID NO: 48. 
     
     
         13 . The method of  claim 11 , wherein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 48. 
     
     
         14 . The method of  claim 11 , wherein the VEGF-C antibody is selected from the group consisting of antibodies 69D09, 103, MM0006-2E65 and 193208. 
     
     
         15 . The method of  claim 10 , wherein the anti-lymphangiogenic agent is antibody that competitively inhibits the binding of antibody 69D09 to VEGF-C. 
     
     
         16 . The method of  claim 10 , wherein the anti-lymphangiogenic agent is a VEGF-D antibody. 
     
     
         17 . The method of  claim 16 , wherein the VEGF-D antibody is selected from the group consisting of antibodies 2F8, 4A5(VD1), 4E10, 5F12, 4H4, 3C10 28AT743.288.48, MM0001-7E79, RM0007-8C35, 78902, 78939 and 90409. 
     
     
         18 . The method of  claim 10 , wherein the anti-lymphangiogenic agent is a soluble VEGFR-3 fragment that binds VEGF-C or VEGF-D. 
     
     
         19 . The method of  claim 10 , wherein the anti-lymphangiogenic agent is a human or humanized antibody. 
     
     
         20 . The method according to  claim 1 , wherein the anti-lymphangiogenic agent is a VEGFR-2 inhibitor. 
     
     
         21 . The method of  claim 1 , wherein said composition further comprises a molecule that inhibits an activity of an inflammatory cytokine selected from the group consisting of IL-1, IL-7, IL23, IL-6 and TNF-α. 
     
     
         22 . The method of  claim 1 , wherein the method further comprises administering an antibiotic to the human. 
     
     
         23 . The method of  claim 22 , wherein the antibiotic is selected from the group consisting of amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, meziocillin, nafcillin, penicillin, piperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, oflaxacin, trovafloxacin, mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, cotrimoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, or tetracycline. 
     
     
         24 . The method of  claim 1 , wherein the eye comprises a tissue or gland in or around the eye selected from the group consisting of ocular tissue, eyelids of the subject, ocular surface, meibomian gland and or lacrimal gland of the human. 
     
     
         25 . The method of  claim 1 , wherein said composition is administered topically to the eye. 
     
     
         26 . The method of  claim 1 , wherein said composition is in the form of a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a film, an emulsion, or a suspension. 
     
     
         27 . The method of  claim 1 , wherein the composition further comprises a compound selected from the group consisting of physiological acceptable salt, poloxamer analogs with carbopol, carbopol/hydroxypropyl methyl cellulose (RP MC), carbopol-methyl cellulose, carboxymethylcellulose (CMC), hyaluronic acid, cyclodextrin, and petroleum.