Nutlin-3a for Treatment of Proliferative Vitreoretinopathy

Abstract

The invention provides compositions and methods for treatment of proliferative vitreoretinopathy.

What is claimed is: 
     
         1 . A composition comprising an agent that
 a. inhibits an intra-ocular reduction of the level of p53 associated with proliferative vitreoretinopathy (PVR), and/or   b. prevents p53 from interacting with human double min 2 (Hdm2),   
       wherein said composition is for inhibiting or reducing the severity of PVR in a subject suffering from or at risk of developing PVR. 
     
     
         2 . The composition of  claim 1 , wherein said agent comprises Nutlin-3a (RG7112/RO5045337) or an analog thereof. 
     
     
         3 . The composition of  claim 1 , wherein said agent comprises a small molecule. 
     
     
         4 . The composition of  claim 1 , wherein said agent comprises a polynucleotide, a polypeptide, or an antibody. 
     
     
         5 . The composition of  claim 2 , wherein said Nutlin-3a, or analog thereof, is administered at a concentration of 0.1 μM, 0.5 μM, 1.0 μM, 2.0 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 50 μM. 
     
     
         6 . The composition of  claim 2 , wherein said Nutlin-3a, or analog thereof, is present in a concentration of 0.1-10% (mg/ml). 
     
     
         7 . The composition of  claim 1 , wherein said composition is administered intravitreally or subconjunctivally. 
     
     
         8 . The composition of  claim 1 , wherein said reduction is a platelet-derived growth factor receptor α (PDGFRα)-mediated reduction. 
     
     
         9 . The composition of  claim 1 , wherein said subject suffering from or at risk of developing PVR has undergone rhegmatogenous retinal detachment surgery. 
     
     
         10 . The composition of  claim 1 , wherein administration of said composition prevents retinal detachment in said subject. 
     
     
         11 . The composition of  claim 1 , wherein administration of said composition reduces the formation of epiretinal membranes in said subject. 
     
     
         12 . The composition of  claim 1 , wherein administration of said composition inhibits the contraction of retinal pigment epithelial (RPE) cells in said subject. 
     
     
         13 . The composition of  claim 1 , wherein said composition is administered every 48 hours, every 24 hours, every 12 hours, or every 6 hours. 
     
     
         14 . The composition of  claim 1 , wherein said composition is administered for 1 day, 3 days, 7 days, 14 days, 30 days, 60 days, 90 days, 120 days, or 365 days. 
     
     
         15 . The composition of  claim 1 , wherein said composition further comprises a pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 1 , wherein the form of said composition is a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a film, an emulsion, or a suspension. 
     
     
         17 . The composition of  claim 1 , wherein said subject is a human. 
     
     
         18 . The composition of  claim 1 , wherein said subject has not been diagnosed with a retinoblastoma. 
     
     
         19 . The composition of  claim 1 , wherein the subject is older than 24 months of age. 
     
     
         20 . The composition of  claim 1 , wherein said agent is Nutlin-3a and the structure of said Nutlin-3a comprises 
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising a Nutlin-3a compound, or analog thereof, and an ophthalmic excipient for inhibiting or reducing the severity of proliferative vitreoretinopathy (PVR). 
     
     
         22 . A method for inhibiting or reducing the severity of proliferative vitreoretinopathy (PVR) comprising:
 identifying a subject suffering from or at risk of developing PVR; and   administering a composition comprising an agent that reduces the intra-ocular reduction of the level of p53, thereby inhibiting or reducing the severity of PVR.   
     
     
         23 . A method for inhibiting or reducing the severity of proliferative vitreoretinopathy (PVR) comprising:
 identifying a subject suffering from or at risk of developing PVR; and   administering a composition comprising an agent that prevents p53 from interacting with human double min 2 (Hdm2).   
     
     
         24 . The method of  claim 22 , wherein said agent that inhibits the intra-ocular reduction of the level of p53 is a polynucleotide, a polypeptide, an antibody, or a small molecule. 
     
     
         25 . The method of  claim 22 , wherein said composition comprises Nutlin-3a (RG7112/RO5045337), or an analog thereof. 
     
     
         26 . The method of  claim 25 , wherein said Nutlin-3a, or analog thereof, is administered at a concentration of 0.1 μM, 0.5 μM, 1.0 μM, 2.0 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 50 μM. 
     
     
         27 . The method of  claim 25 , wherein said Nutlin-3a, or analog thereof, is present in a concentration of 0.1-10% (mg/ml). 
     
     
         28 . The method of  claim 22 , wherein said composition is administered intravitreally or subconjunctivally. 
     
     
         29 . The method of  claim 22 , wherein said intra-ocular reduction is a platelet-derived growth factor receptor α (PDGFRα)-mediated reduction. 
     
     
         30 . The method of  claim 22 , wherein said subject suffering from or at risk of developing PVR has undergone rhegmatogenous retinal detachment surgery. 
     
     
         31 . The method of  claim 22 , wherein the subject is older than 24 months of age. 
     
     
         32 . The method of  claim 22 , wherein said composition prevents retinal detachment in said subject. 
     
     
         33 . The method of  claim 22 , wherein said composition reduces the formation of epiretinal membranes in said subject. 
     
     
         34 . The method of  claim 22 , wherein said composition inhibits the contraction of retinal pigment epithelial (RPE) cells in said subject. 
     
     
         35 . The method of  claim 22 , wherein said composition is administered every 48 hours, every 24 hours, every 12 hours, or every 6 hours. 
     
     
         36 . The method of  claim 22 , wherein said composition is administered for 1 day, 3 days, 7 days, 14 days, 30 days, 60 days, 90 days, 120 days, or 365 days. 
     
     
         37 . The method of  claim 22 , wherein said composition further comprises a pharmaceutically acceptable carrier. 
     
     
         38 . The method of  claim 22 , wherein the form of said composition is a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a film, an emulsion, or a suspension. 
     
     
         39 . The method of  claim 22 , wherein said subject is a human. 
     
     
         40 . The method of  claim 22 , wherein said subject has not been diagnosed with a retinoblastoma. 
     
     
         41 . The method of  claim 22 , wherein the composition comprises Nutlin-3a, and wherein the structure of said Nutlin-3a comprises 
       
         
           
           
               
               
           
         
       
     
     
         42 . A pharmaceutical composition comprising a Nutlin-3a compound, or analog thereof, and an ophthalmic excipient.