Modified fibroblast growth factors for the treatment of ocular disorders

Abstract

Described herein are modified fibroblast growth factors (FGFs), pharmaceutical compositions, ophthalmic formulations, and medicaments that include such modified FGFs, and methods of using such modified FGFs to treat ocular diseases, disorders, or conditions.

What is claimed is: 
     
         1 . A method of treating or preventing an ocular disease, disorder or condition in a mammal comprising administering to the mammal a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134. 
     
     
         2 . The method of  claim 1 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         3 . The method of  claim 1 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         4 . The method of  claim 1 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         5 . The method of  claim 1 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         6 . The method of  claim 1 , wherein the modified FGF-1 is thermostable. 
     
     
         7 . The method of  claim 1 , wherein the modified FGF-1 comprises a reduced number of reactive thiols. 
     
     
         8 . The method of  claim 1 , wherein the method is performed without administering heparin to the mammal. 
     
     
         9 . The method of one of  claim 1 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the cornea or ocular surface. 
     
     
         10 . The method of  claim 9 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal endothelium. 
     
     
         11 . The method of  claim 10 , wherein the disease, disorder, or condition of the corneal endothelium is Fuch's dystrophy, bullous keratopathy, congenital hereditary endothelial dystrophy 1, congenital hereditary endothelial dystrophy 2, posterior polymorphous corneal dystrophy, or a dry eye syndrome. 
     
     
         12 . The method of  claim 11 , wherein the ocular disease, disorder or condition is Fuch's dystrophy. 
     
     
         13 . The method of  claim 9 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal epithelium. 
     
     
         14 . The method of  claim 13 , wherein the condition of the corneal epithelium is a dry eye syndrome or corneal epithelial damage from corneal surgery or transplantation. 
     
     
         15 . The method of  claim 14 , wherein the corneal surgery is photorefractive keratotomy (PRK) or laser-assisted in situ keratomileusis (LASIK). 
     
     
         16 . The method of  claim 9 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal stroma. 
     
     
         17 . The method of  claim 16 , wherein the disease, disorder, or condition of the corneal stroma is keratoconus, lattice corneal dystrophy, granular corneal dystrophy, macular corneal dystrophy, Schnyder crystalline corneal dystrophy, congenital stromal corneal dystrophy, or fleck corneal dystrophy. 
     
     
         18 . The method of  claim 1 , wherein the modified FGF-1 is administered topically, by microneedle into the cornea, or intracamerally. 
     
     
         19 . The method of  claim 1 , wherein the modified FGF-1 is administered by an eye drop. 
     
     
         20 . A method of treating or preventing a disease, disorder or condition of the cornea in a mammal comprising administering to the mammal a pharmaceutical composition comprising:
 a. a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134; and   b. a pharmaceutically acceptable carrier, excipient, or diluent.   
     
     
         21 . The method of  claim 20 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         22 . The method of  claim 20 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         23 . The method of  claim 20 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         24 . The method of  claim 20 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         25 . The method of  claim 20 , wherein the modified FGF-1 is thermostable. 
     
     
         26 . The method of  claim 20 , wherein the modified FGF-1 comprises a reduced number of reactive thiols. 
     
     
         27 . The method of  claim 20 , wherein the pharmaceutical composition is free of heparin. 
     
     
         28 . The method of  claim 20 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the cornea or ocular surface. 
     
     
         29 . The method of  claim 28 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal endothelium. 
     
     
         30 . The method of  claim 29 , wherein the disease, disorder, or condition of the corneal endothelium is Fuch's dystrophy, bullous keratopathy, congenital hereditary endothelial dystrophy 1, congenital hereditary endothelial dystrophy 2, posterior polymorphous corneal dystrophy, or a dry eye syndrome. 
     
     
         31 . The method of  claim 30 , wherein the ocular disease, disorder or condition is Fuch's dystrophy. 
     
     
         32 . The method of  claim 28 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal epithelium. 
     
     
         33 . The method of  claim 32 , wherein the condition of the corneal epithelium is a dry eye syndrome or corneal epithelial damage from corneal surgery or transplantation. 
     
     
         34 . The method of  claim 33 , wherein the corneal surgery is photorefractive keratotomy (PRK) or laser-assisted in situ keratomileusis (LASIK). 
     
     
         35 . The method of  claim 28 , wherein the ocular disease, disorder or condition is a disease, disorder, or condition of the corneal stroma. 
     
     
         36 . The method of  claim 35 , wherein the disease, disorder, or condition of the corneal stroma is keratoconus, lattice corneal dystrophy, granular corneal dystrophy, macular corneal dystrophy, Schnyder crystalline corneal dystrophy, congenital stromal corneal dystrophy, or fleck corneal dystrophy. 
     
     
         37 . The method of  claim 20 , wherein the pharmaceutical composition is a liquid ophthalmic formulation. 
     
     
         38 . The method of  claim 37 , wherein the ophthalmic formulation is administered topically, by microneedle into the cornea, or intracamerally. 
     
     
         39 . The method of  claim 37 , wherein the ophthalmic formulation is administered by an eye drop. 
     
     
         40 . A method of transplanting corneal cells to a mammal comprising enhancing the success of cell transplantation by treating the corneal cells to be transplanted with a modified FGF-1 prior to, during or after transplanting the corneal cells to the mammal, the modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134. 
     
     
         41 . The method of  claim 40 , wherein the corneal cells comprise cells from donor corneal tissue within the donor cornea. 
     
     
         42 . The method of  claim 40 , wherein the corneal cells comprise cells derived from progenitor cells. 
     
     
         43 . The method of  claim 40 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         44 . The method of  claim 40 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         45 . The method of  claim 40 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         46 . The method of  claim 40 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         47 . An ophthalmic formulation comprising:
 a. a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134; and   b. a pharmaceutically acceptable carrier, excipient, or diluent.   
     
     
         48 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         49 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         50 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         51 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         52 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 is thermostable. 
     
     
         53 . The ophthalmic formulation of  claim 47 , wherein the modified FGF-1 comprises a reduced number of reactive thiols. 
     
     
         54 . The ophthalmic formulation of  claim 47 , wherein the ophthalmic formulation is free of heparin. 
     
     
         55 . The ophthalmic formulation of  claim 47 , wherein the ophthalmic formulation is a liquid formulation. 
     
     
         56 . A kit comprising:
 a. an ophthalmic formulation comprising:
 i. a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134; and 
 ii. a pharmaceutically acceptable carrier, excipient, or diluent; and 
   b. a container.   
     
     
         57 . The kit of  claim 56 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         58 . The kit of  claim 56 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         59 . The kit of  claim 56 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         60 . The kit of  claim 56 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         61 . The kit of  claim 56 , wherein the modified FGF-1 is thermostable. 
     
     
         62 . The kit of  claim 56 , wherein the modified FGF-1 comprises a reduced number of reactive thiols. 
     
     
         63 . The kit of  claim 56 , wherein the ophthalmic formulation is free of heparin. 
     
     
         64 . The kit of  claim 56 , wherein the ophthalmic formulation is a liquid formulation. 
     
     
         65 . A method of modulating the activity of one or more fibroblast growth factor receptors in a corneal endothelial cell comprising contacting the corneal endothelial cell with a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134. 
     
     
         66 . The method of  claim 65 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         67 . The method of  claim 65 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         68 . The method of  claim 65 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         69 . The method of  claim 65 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         70 . The method of  claim 65 , wherein the modified FGF-1 is thermostable. 
     
     
         71 . The method of  claim 65 , wherein the modified FGF-1 comprises a reduced number of reactive thiols. 
     
     
         72 . The method of  claim 65  wherein the modulating increases the activity of the one or more FGFRs. 
     
     
         73 . The method  claim 65  wherein the modulating increases the proliferation of the corneal endothelial cell. 
     
     
         74 . A method of preventing scarring during tissue regeneration comprising administering a modified FGF-1 comprising one or more mutations of human FGF-1 at positions 12, 16, 66, 117, and 134. 
     
     
         75 . The method of  claim 74 , wherein the modified FGF-1 comprises one or more mutations selected from the group consisting of: Lys12Val, Pro134Val, Ala66Cys, Cys117Val, and Pro134Val. 
     
     
         76 . The method of  claim 74 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 2. 
     
     
         77 . The method of  claim 74 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 3. 
     
     
         78 . The method of  claim 74 , wherein the modified FGF-1 comprises the sequence of SEQ ID NO: 4. 
     
     
         79 . The method of  claim 74 , wherein the modified FGF-1 is adminstered in a suitable ohpthalmic formulation. 
     
     
         80 . The method of  claim 74 , wherein the modified FGF-1 is administered to a mammal after undergoing a trabeculectomy.