Methods for treating eye disorders

Abstract

The present invention relates to compositions and methods for inhibiting loss of a retinal ganglion cell in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA which down regulates expression of a target gene associated with loss of the retinal ganglion cell, thereby inhibiting loss of the retinal ganglion cell in the subject. The methods of the invention also relate to the use of chemically modified siRNA compounds possessing structural motifs which down-regulate the expression of human genes expressed in retinal tissue in the mammalian eye.

1 . A method for inhibiting loss of a retinal ganglion cell in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA which down regulates expression of a target gene associated with loss of the retinal ganglion cell, thereby inhibiting loss of the retinal ganglion cell in the subject. 
     
     
         2 . The method of  claim 1 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         3 . The method according to any on of  claim 1  or  2 , wherein the subject is a human. 
     
     
         4 . The method according to any one of  claims 1  to  3 , wherein the subject is suffering from an ocular disease, an ocular disorder or an ocular injury or at risk of developing an ocular disease, an ocular disorder, or an ocular injury. 
     
     
         5 . The method according to any one of  claims 1  to  4 , wherein said loss of a retinal ganglion cell is associated with an ocular disease, an ocular disorder, or an ocular injury in the subject. 
     
     
         6 . The method according to  claim 4  or  5 , wherein said ocular disease, disorder, or injury comprises neurodegeneration. 
     
     
         7 . The method according to anyone of  claims 1  to  6 , wherein the ophthalmic composition is formulated as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens. 
     
     
         8 . The method according to  claim 7 , wherein the ophthalmic composition is formulated as an eye drop. 
     
     
         9 . The method according to anyone of  claims 4  to  8 , wherein said disease, disorder, or injury is selected from a group consisting of glaucoma, dry eye, diabetic retinopathy (DR), diabetic macular edema (DME), age related macular degeneration (AMD), optic neuritis, central retinal vein occlusion, brunch retinal vein occlusion, ischemic optic neuropathy, optic nerve injury, retinopathy of prematurity (ROP) or retinitis pigmentosa (RP), retinal ganglion degeneration, macular degeneration, hereditary optic neuropathy, metabolic optic neuropathy, optic neuropathy due to a toxic agent or neuropathy caused by adverse drug reactions or vitamin deficiency. 
     
     
         10 . The method according to  claim 9 , wherein the said disease, disorder or injury is glaucoma and the target gene is set forth in any one of SEQ ID NO:1-35. 
     
     
         11 . The method according to  claim 10 , wherein the target gene is set forth in any one of SEQ ID NO:1-2, SEQ ID NO:4, SEQ ID NO:6-7, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:19-20, SEQ ID NO:21 and SEQ ID NO:28-29. 
     
     
         12 . The method according to  claim 11 , wherein the target gene is set forth in any one of SEQ ID NO:1-SEQ ID NO:2. 
     
     
         13 . The method according to  claim 9 , wherein said disease, disorder or injury is dry-eye and the target gene is set forth in any one of SEQ ID NO:5, SEQ ID NO:8-10, SEQ ID NO:26-27 and SEQ ID NO:30-44. 
     
     
         14 . The method according to  claim 13 , wherein the target gene is set forth in any one of SEQ ID NO:36-SEQ ID NO:44. 
     
     
         15 . The method according to  claim 9 , wherein said disease, disorder or injury is age related macular degeneration (AMD) and the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         16 . The method according to  claim 15 , wherein the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:12 and SEQ ID NO:47. 
     
     
         17 . The method according to  claim 9 , wherein said disease, disorder or injury is diabetic macular edema (DME) and the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         18 . The method according to  claim 17 , wherein the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:12 and SEQ ID NO:47. 
     
     
         19 . The method according to  claim 9 , wherein said disease, disorder or injury is diabetic retinopathy (DR) and the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         20 . The method according to  claim 19 , wherein the target gene is set forth in any one of SEQ ID NO: 48-53. 
     
     
         21 . The method according to  claim 9 , wherein said disease, disorder or injury is retinitis pigmentosa (RP) and the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:14, SEQ ID NO:26-35 and SEQ ID NO:54-58. 
     
     
         22 . The method according to  claim 21 , wherein the target gene is set forth in any one of SEQ ID NO: 56-57. 
     
     
         23 . A method of rescuing a retinal ganglion cell from apoptosis in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene in the retina of the subject, thereby rescuing retinal ganglion cell from apoptosis in the subject. 
     
     
         24 . The method of  claim 23 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         25 . A method for promoting survival of a retinal ganglion cell in a subject displaying signs or symptoms of an ocular neuropathy, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene that promotes survival of a retinal ganglion cell, thereby promoting survival of a retinal ganglion cell in the subject. 
     
     
         26 . The method of  claim 25 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         27 . The method according to  claim 25  or  26 , wherein the signs or symptoms are mediated by apoptosis. 
     
     
         28 . A method for preventing, treating or alleviating the effects of an ocular disease associated with death of a retinal ganglion cell in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene associated with the ocular disease, thereby preventing, treating or alleviating the effects of an ocular disease associated with death of a retinal ganglion cell in the subject. 
     
     
         29 . The method of  claim 28 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         30 . A method for treating or preventing retinal ganglion cell death in a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition which comprises: (a) a therapeutically effective amount of at least one siRNA to a target gene associated with retinal ganglion cell death, and (b) a pharmaceutically acceptable excipient or carrier or mixture thereof, and thereby treating or preventing retinal ganglion cell death in the subject. 
     
     
         31 . The method of  claim 30 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         32 . A method for preventing retinal ganglion cell death mediated by elevated intraocular pressure (IOP) in the eye of a subject, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene in the retina of the subject, thereby preventing retinal ganglion cell death in the subject. 
     
     
         33 . The method of  claim 32 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         34 . A method of delaying, preventing or rescuing a retinal cell from death in a subject suffering from elevated IOP comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene associated with death of the RGC in the retina of the subject, thereby delaying, preventing or rescuing the retinal cell from injury or death and wherein intraocular pressure (IOP) remains substantially elevated. 
     
     
         35 . The method according to  claim 34 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         36 . The method according to anyone of  claims 32  to  35 , wherein the subject is afflicted with glaucoma. 
     
     
         37 . A method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, comprising non-invasively administering to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene associated with the retinal ganglion cell loss or damage, thereby treating the subject or reducing retinal ganglion cell death in the subject. 
     
     
         38 . The method according to  claim 37 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         39 . A method for attenuating retinal ganglion cell loss and providing ocular neuroprotection to a subject in need thereof, comprising non-invasively applying to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene associated with retinal ganglion cell loss, thereby attenuating retinal ganglion cell loss and providing ocular neuroprotection to the subject. 
     
     
         40 . The method according to  claim 39 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         41 . A method for preventing visual field loss associated with loss of retinal ganglion cells in a subject, comprising non-invasively administering to the surface of the eye of the subject an ophthalmic composition comprising a therapeutically effective amount of at least one siRNA to a target gene in the retina of the subject, thereby preventing visual field loss in the subject. 
     
     
         42 . The method according to  claim 41 , wherein the target gene is set forth in any one of SEQ ID NO:1-58. 
     
     
         43 . An ophthalmic composition for non-invasive treatment of an ocular disease associated with loss of a retinal ganglion cell in a subject, comprising: (a) a therapeutically effective amount of at least one siRNA to a target gene associated with the ocular disease, and (b) a pharmaceutically acceptable excipient or carrier or mixture thereof. 
     
     
         44 . A topical ophthalmic pharmaceutical composition for non-invasive treatment of an ocular disease associated with pathological abnormalities/changes in the tissues of the visual system, comprising: (a) a therapeutically effective amount of at least one siRNA to a target gene associated with the ocular disease, wherein the target gene is set forth in any one of SEQ ID NO:1-58, and (b) a pharmaceutically acceptable excipient or carrier or mixture thereof. 
     
     
         45 . The composition of  claim 44 , wherein the ocular disease is associated with loss of retinal ganglion cells in the visual system. 
     
     
         46 . A topical ophthalmic pharmaceutical composition for use in treating a subject afflicted with ocular disease associated with death of retinal ganglion cells, which comprises: (a) a therapeutically effective amount of at least one siRNA to a target gene associated with the ocular disease, wherein the target gene is set forth in any one of SEQ ID NO:1-58, and (b) a pharmaceutically acceptable excipient or carrier or mixture thereof. 
     
     
         47 . The composition according to any one of  claims 43  to  46 , wherein siRNA is present at a final concentration of about 5 μg/μl to about 60 μg/μl by volume of the composition. 
     
     
         48 . The composition according to  claim 47 , wherein siRNA is present at a final concentration of about 6.6 μg/μl by volume of the composition. 
     
     
         49 . The composition or composition according to  claim 47 , wherein siRNA is present at a final concentration of about 25 μg/μl by volume of the composition. 
     
     
         50 . The composition according to  claim 47 , wherein siRNA is present at a final concentration of about 33.3 μg/μl by volume of the composition. 
     
     
         51 . The composition according to  claim 47 , wherein siRNA is present at a final concentration of about 50 μg/μl by volume of the composition. 
     
     
         52 . The composition according to any one of  claims 43  to  51 , wherein said ocular disease is selected from a group comprising glaucoma, dry eye, diabetic retinopathy (DR), diabetic macular edema (DME), age related macular degeneration (AMD), optic neuritis, central retinal vein occlusion, brunch retinal vein occlusion, ischemic optic neuropathy, optic nerve injury, retinopathy of prematurity (ROP) or retinitis pigmentosa (RP), retinal ganglion degeneration, macular degeneration, hereditary optic neuropathy, metabolic optic neuropathy, neuropathy due to a toxic agent or that caused by adverse drug reactions or vitamin deficiency. 
     
     
         53 . The composition according to anyone of  claims 43  to  52 , wherein the composition is formulated as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens. 
     
     
         54 . The method according to  claim 53 , wherein the composition is formulated as an eye drop. 
     
     
         55 . A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to any one of  claims 43  to  54  in a container; and (b) instructions for using the composition to treat an ocular disease. 
     
     
         56 . Use of a pharmaceutical composition according to any one of  claims 43  to  54  in the manufacture of a medicament for promoting retinal ganglion cell survival. 
     
     
         57 . A method of treating glaucoma in a subject in need of treatment, the method comprising topically administering to the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:1-35. 
     
     
         58 . The method according to  claim 57 , wherein the target gene is set forth in any one of SEQ ID NO:1-2, SEQ ID NO:4, SEQ ID NO:6-7, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:19-20, SEQ ID NO:21 and SEQ ID NO:28-29. 
     
     
         59 . The method according to  claim 58 , wherein the target gene is set forth in any one of SEQ ID NO:1-SEQ ID NO:2. 
     
     
         60 . A method of treating dry-eye in a subject in need of treatment, the method comprising topically administering to the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:5, SEQ ID NO:8-10, SEQ ID NO:26-27 and SEQ ID NO:30-44. 
     
     
         61 . The method according to  claim 60 , wherein the target gene is set forth in any one of SEQ ID NO:36-SEQ ID NO:44. 
     
     
         62 . A method of treating age related macular degeneration (AMD) in a subject in need of treatment, the method comprising topically administering to the surface of the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         63 . The method according to  claim 62 , wherein the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:12 and SEQ ID NO:47. 
     
     
         64 . A method of treating diabetic macular edema (DME) in a subject in need of treatment, the method comprising topically administering to the surface of the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         65 . The method according to  claim 64 , wherein the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:12 and SEQ ID NO:47. 
     
     
         66 . A method of treating diabetic retinopathy (DR) in a subject in need of treatment, the method comprising topically administering to the surface of the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:1-3, SEQ ID NO:5-10, SEQ ID NO:12-13, SEQ ID NO:24-27, SEQ ID NO:30-35, SEQ ID NO:45-53. 
     
     
         67 . The method according to  claim 66 , wherein the target gene is set forth in any one of SEQ ID NO: 48-53. 
     
     
         68 . A method of treating retinitis pigmentosa (RP) in a subject in need of treatment, the method comprising topically administering to the surface of the eye of the subject a therapeutically effective amount of at least one siRNA to a target gene in the eye of the subject, wherein the target gene is set forth in any one of SEQ ID NO:3, SEQ ID NO:14, SEQ ID NO:26-35 and SEQ ID NO:54-58. 
     
     
         69 . The method according to  claim 68 , wherein the target gene is set forth in any one of SEQ ID NO: 56-57. 
     
     
         70 . The method according to any one of  claims 57  to  69  wherein the siRNA is formulated for topical administration to the surface of the eye. 
     
     
         71 . The method according to any one of  claims 57  to  69 , wherein the siRNA is formulated as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens. 
     
     
         72 . The method according to  claim 71 , wherein the siRNA is formulated as an eye drop. 
     
     
         73 . The method according to any one of  claims 57  to  72 , wherein the siRNA is administered as an eye drop.