Methods and compositions for preserving retinal ganglion cells

Abstract

Provided are methods and compositions for maintaining the viability of retinal ganglion cells in a subject with an ocular disorder including, for example, glaucoma and optic nerve injury. The viability of the retinal ganglion cells can be preserved by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject having an eye with the ocular condition. The compositions, when administered, maintain the viability of the cells and/or promote axon regeneration, thereby minimizing the loss of vision or visual function associated with the ocular disorder.

We claim: 
     
         1 . A method of preserving visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of the eye with the condition, the method comprising:
 (a) administering to the eye of the subject an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to preserve the viability of retinal ganglion cells disposed within the retina of the eye; and   (b) after step (a), measuring visual function of the eye.   
     
     
         2 . The method of  claim 1 , wherein, after administration of the necrosis inhibitor and the apoptosis inhibitor, the visual function of the eye is preserved or improved relative to the visual function prior to administration of the necrosis inhibitor and the apoptosis inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the ocular condition is selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion. 
     
     
         4 . (canceled) 
     
     
         5 . A method of preserving visual function of an eye of a subject with an ocular condition selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of the eye, the method comprising:
 reducing the production and/or activity of a RIP-1 kinase and/or a RIP-3 kinase in the eye thereby preserving the viability of the retinal ganglion cells disposed with the retina of the eye.   
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 5 , wherein the reduction in the production and/or activity of the RIP-1 kinase and/or the RIP-3 kinase is achieved by administering an effective amount of a RIP kinase inhibitor. 
     
     
         8 . The method of  claim 7 , wherein the RIP kinase inhibitor is a necrostatin. 
     
     
         9 . The method of  claim 7 , wherein, after step (a), the visual function of the eye is preserved or improved relative to the visual function of the eye prior to step (a). 
     
     
         10 . The method of  claim 2 , wherein the visual function is visual acuity. 
     
     
         11 . The method of  claim 10 , wherein the ocular condition is a condition selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion. 
     
     
         12 . A method for promoting axonal regeneration in an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of an eye with the condition, the method comprising:
 administering to the eye of the subject an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to promote the regeneration of a retinal ganglion cell axon within the retina of the eye.   
     
     
         13 . The method of  claim 12 , further comprising, after the administration of the necrosis inhibitor and the apoptosis inhibitor, measuring visual function of the eye. 
     
     
         14 . The method of  claim 13 , wherein the visual function of the eye is preserved or improved relative to the visual function prior to administration of the necrosis inhibitor and the apoptosis inhibitor. 
     
     
         15 . The method of  claim 12 , wherein the ocular condition is selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion. 
     
     
         16 . The method of  claim 3 , wherein the ocular condition is glaucoma. 
     
     
         17 . The method of  claim 1 , wherein the necrosis inhibitor is a necrostatin. 
     
     
         18 . The method of  claim 17 , wherein the necrostatin is selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necreostatin-5, and necrostatin-7, or a combination thereof. 
     
     
         19 . The method of  claim 18 , wherein the necrostatin is necrostatin-1. 
     
     
         20 . The method of  claim 17 , wherein the necrostatin is administered to provide a final concentration of necrostatin in the eye greater than about 10 μM. 
     
     
         21 - 25 . (canceled) 
     
     
         26 . The method of  claim 17 , wherein from about 0.05 mg to about 2 mg of necrostatin is administered. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the apoptosis inhibitor is a pan-caspase inhibitor. 
     
     
         30 . The method of  claim 29 , wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof. 
     
     
         31 - 36 . (canceled) 
     
     
         37 . The method of  claim 29 , wherein from about 0.15 mg to about 1.5 mg of the pan-caspase inhibitor is administered. 
     
     
         38 - 39 . (canceled) 
     
     
         40 . The method of  claim 17 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered to the eye. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 17 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered by intraocular injection. 
     
     
         43 . The method of  claim 42 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered intravitreally. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 17 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered sequentially or simultaneously. 
     
     
         46 . The method of  claim 17 , wherein the necrostatin is a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein 
         X is O or S; 
         R 1  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6  alkoxyl, or halogen; and 
         R 2  is hydrogen or C 1 -C 6 alkyl. 
       
     
     
         47 . The method of  claim 17 , wherein the necrostatin is a compound of Formula I-A:— 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or prodrug thereof, 
         wherein R 1  is H, alkyl, alkoxyl, or a halogen and R 2  is H or an alkyl. 
       
     
     
         48 . The method of  claim 17 , wherein the necrostatin is a compound selected from the group consisting of a compound of Formula I-B: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof a compound of Formula I-C 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof and a compound of Formula I-D 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         49 - 64 . (canceled)