Prevention and treatment of retinal ischemia and edema

Abstract

The present invention relates to methods of treating retinopathy, retinal ischemia and/or retinal edema comprising administering an integrin or integrin subunit antagonist, leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist, a selectin antagonist or adhesion molecule antagonist.

What is claimed is:  
     
         1 . A method for reducing or preventing retinal injury in a mammal, wherein the injury involves retinal edema or retinal ischemia, comprising administering to the mammal a compound that inhibits the binding of a leukocyte to an endothelial cell or to another leukocyte, wherein a reduction in retinal edema or retinal ischemia occurs.  
     
     
         2 . The method of  claim 1 , wherein the compound is an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist or a leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist.  
     
     
         3 . The method of  claim 2 , wherein the integrin antagonist is selected from a group consisting of: LFA-1 antagonist, Mac-1 antagonist and p150,95 antagonist.  
     
     
         4 . The method of  claim 3 , wherein the integrin antagonist comprises an integrin subunit antagonist.  
     
     
         5 . The method of  claim 4 , wherein the integrin subunit antagonist comprises a CD18 antagonist, CD11a antagonist, or a CD11b antagonist.  
     
     
         6 . The method of  claim 2 , wherein the selectin antagonist is selected from a group consisting of: P-selectin antagonist, E-selectin antagonist and L-selectin antagonist.  
     
     
         7 . The method of  claim 2 , wherein the adhesion molecule antagonist is selected from the group consisting of ICAM-1 antagonist, ICAM-2 antagonist, ICAM-3 antagonist, PCAM antagonist, and VCAM antagonist.  
     
     
         8 . The method of  claim 2 , wherein the leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist is selected from a group consisting of: TNF-1α, IL-1β, MCP-1 and VEGF antagonist.  
     
     
         9 . A method for reducing or preventing retinal injury in a mammal, comprising administering to the mammal an adhesion molecule antagonist and/or an integrin antagonist, wherein the adhesion molecule antagonist and/or the integrin antagonist inhibits leukocyte interaction, thereby reducing or preventing retinal injury.  
     
     
         10 . The method of  claim 9 , wherein the adhesion molecule antagonist is an ICAM-1 antagonist, ICAM-2 antagonist, ICAM-3 antagonist, PCAM antagonist and VCAM antagonist.  
     
     
         11 . The method of  claim 9 , wherein the antagonist is an antibody or antibody fragment specific for ICAM-1.  
     
     
         12 . The method of  claim 9 , wherein the antagonist is an antisense molecule that hybridizes to the nucleic acid sequence that encodes ICAM-1, or a peptide mimetic molecule, ribozyme, an aptamer or a small molecule antagonist that inhibits ICAM-1.  
     
     
         13 . The method of  claim 9 , wherein the integrin antagonist is selected from a group consisting of: LFA-1 antagonist, Mac-1 antagonist and p150,95 antagonist.  
     
     
         14 . The method of  claim 13 , wherein the integrin antagonist comprises an integrin subunit antagonist.  
     
     
         15 . The method of  claim 14 , wherein the integrin subunit antagonist comprises a CD18 antagonist, a CD11a antagonist, and/or a CD11b antagonist.  
     
     
         16 . The method of  claim 15 , wherein the antagonist is an antisense molecule that hybridizes to the nucleic acid sequence that encodes CD18, CD11a, and/or CD11b, or a peptide mimetic molecule, a ribozyme, an aptamer or a small molecule antagonist that inhibits CD18, CD11b or CD11b.  
     
     
         17 . The method of  claim 9 , wherein the adhesion molecule antagonist and/or the integrin subunit antagonist is administered in a pharmaceutically acceptable carrier.  
     
     
         18 . A method for preventing or treating an individual having retinal injury, wherein the injury is associated with retinal edema and/or retinal ischemia, comprising administering to the individual a compound that inhibits Mac-1 or a pathway thereof, wherein a reduction in retinal edema and/or retinal ischemia occurs.  
     
     
         19 . The method of  claim 18 , wherein the compound inhibits ICAM-1, CD18, CD11a, CD11b, and/or VEGF.  
     
     
         20 . The method of  claim 19 , wherein a decrease of ischemia and/or edema occurs.  
     
     
         21 . The method of  claim 20 , wherein the decrease of ischemia and/or edema is between about 10% and about 90%.  
     
     
         22 . The method of  claim 18 , wherein the individual has diabetic retinopathy.  
     
     
         23 . A method for treating an individual having diabetic retinopathy comprising administering to the individual a compound that inhibits Mac-1 or a pathway thereof, wherein leukocyte interaction is reduced.  
     
     
         24 . The method of  claim 23 , wherein the compound comprises an antibody, an antibody fragment, a peptide mimetic molecule, an antisense molecule, a ribozyme, an aptamer and/or a small molecule antagonist.  
     
     
         25 . The method of  claim 24 , wherein the compound inhibits ICAM-1, CD18, CD11a, CD11b, and/or VEGF.  
     
     
         26 . A method for treating an individual having diabetic retinopathy comprising 10 administering to the individual an ICAM-1, CD18, CD11a, CD11b and/or VEGF antagonist, wherein the ICAM-1, CD18, CD11a, CD11b and/or VEGF antagonist inhibits leukocyte interaction.  
     
     
         27 . The method of  claim 26 , wherein the antagonist is an antibody or antibody fragment specific for ICAM-1 and/or VEGF.  
     
     
         28 . The method of  claim 26 , wherein the antagonist is an antisense molecule that hybridizes to the nucleic acid sequence that encodes ICAM-1, CD18, CD11a, CD11b and/or VEGF.  
     
     
         29 . The method of  claim 27 , wherein a decrease of ischemia and/or edema occurs.  
     
     
         30 . The method of  claim 29 , wherein the decrease of ischemia and/or edema is between about 10% and about 90%.  
     
     
         31 . A method for treating an individual with retinal edema comprising administering to the individual an ICAM-1, CD18, CD11a, CD11b and/or VEGF antagonist, wherein a decrease in the retinal edema occurs.  
     
     
         32 . The method of  claim 31 , wherein the antagonist is an antibody or antibody fragment that is specific for ICAM-1 and/or VEGF.  
     
     
         33 . The method of  claim 31 , wherein the antagonist is an antisense molecule that hybridizes to a nucleic acid sequence that encodes ICAM-1, CD18, CD11a, CD11b and/or VEGF.  
     
     
         34 . The method of  claim 31 , wherein the decrease of a edema is between about 10% and about 90%.  
     
     
         35 . A method for treating an individual with retinal ischemia comprising administering to the individual an ICAM-1, CD18, CD11a, CD11b and/or VEGF antagonist, wherein a decrease in ischemia occurs.  
     
     
         36 . The method of  claim 35 , wherein the antagonist is an antibody or antibody fragment specific for ICAM-1 and/or VEGF.  
     
     
         37 . The method of  claim 35 , wherein the decrease of ischemia is between about 10% and about 90%.  
     
     
         38 . The method of  claim 35 , wherein the antagonist is an antisense molecule that hybridizes to a nucleic acid sequence which encodes ICAM-1, CD18, CD11a, CD11b and/or VEGF.  
     
     
         39 . The method of treating diabetic retinopathy in an individual, comprising administering to the individual an ICAM-1, a CD18, CD11a, CD11b and/or VEGF antagonist and at least one additional antagonist that inhibits the binding of a leukocyte to an endothelial cell or to another leukocyte.  
     
     
         40 . The method of  claim 39 , wherein the additional antagonist is an integrin antagonist, selectin antagonist, a leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist, or another adhesion molecule antagonist.  
     
     
         41 . The method of  claim 40 , wherein the integrin is selected from a group consisting of: LFA-1, Mac-1 and p150,95.  
     
     
         42 . The method of  claim 41 , wherein the integrin antagonist comprises an integrin subunit antagonist.  
     
     
         43 . The method of  claim 42 , wherein the integrin subunit antagonist comprises a CD18 antagonist, a CD11a antagonist, or a CD11b antagonist.  
     
     
         44 . The method of  claim 40 , wherein the selectin is selected from a group consisting of: P-selectin, E-selectin and L-selectin.  
     
     
         45 . The method of  claim 40 , wherein the leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist is selected from a group consisting of: TNF-1α, IL-1β, MCP-1 and another VEGF antagonist.  
     
     
         46 . The method of  claim 40 , wherein the adhesion molecule antagonist is a PCAM antagonist, VCAM antagonist, an ICAM-2 antagonist, an ICAM-3 antagonist or another ICAM-1 antagonist.  
     
     
         47 . A method of inhibiting leukocyte interaction, comprising contacting a leukocyte, an endothelial cell or a leukocyte adhesion-inducing cytokine with a compound, wherein the compound is selected from the group consisting of: an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist, leukocyte adhesion-inducing cytokine antagonist and growth factor antagonist  
     
     
         48 . The method of  claim 47 , wherein the leukocyte adhesion-inducing cytokine is TNF-α, IL-1β or MCP-1.  
     
     
         49 . A method of inhibiting leukocyte interaction, comprising contacting an endothelial cell with an adhesion molecule antagonist.  
     
     
         50 . The method of  claim 49 , wherein the adhesion molecule antagonist is specific to ICAM-1.  
     
     
         51 . A method of inhibiting leukocyte interaction, comprising contacting an endothelial cell with an integrin subunit antagonist.  
     
     
         52 . The method of  claim 52 , wherein the integrin subunit antagonist is specific to CD18, CD11a, and/or CD11b.  
     
     
         53 . A method of inhibiting leukocyte interaction, comprising contacting a leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist.  
     
     
         54 . The method of  claim 53 , wherein the leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist is selected from a group consisting of: TNF-1α, IL-1β, MCP-1 and VEGF antagonist.  
     
     
         55 . A method of preventing or reducing retinal leukostasis an a mammal comprising administering to the mammal an effective amount of an ICAM, CD18, CD11a, CD11b and/or VEGF antagonist.  
     
     
         56 . The method of  claim 55 , wherein the ICAM antagonist is an ICAM-1 antagonist.  
     
     
         57 . The method of  claim 55 , wherein the antagonist is an antibody or antibody fragment specific for ICAM-1 and/or VEGF.  
     
     
         58 . The method of  claim 55 , wherein the antagonist is an antisense molecule that hybridizes to a nucleic acid sequence which encodes ICAM-1, CD18, CD11a, CD11b and/or VEGF.  
     
     
         59 . The method of  claim 55 , wherein retinal leukostasis is reduced by between about 10% and 90%.  
     
     
         60 . A method of decreasing retinal leukocyte adhesion in a mammal, comprising administering to the mammal an effective amount of an antagonist that is specific for CD11a, CD11b, CD18 or a combination thereof.  
     
     
         61 . The method of  claim 60 , wherein retinal leukocyte adhesion is decreased between about 10% and 90%.  
     
     
         62 . A method of treating or preventing neovascularization in a mammal, comprising administering to the mammal a CD18 antagonist and an ICAM-1 antagonist, wherein neovascularization is reduced.  
     
     
         63 . The method of  claim 62 , wherein the CD18 antagonist or the ICAM-1 antagonist is an antibody, an antibody fragment, a peptide mimetic molecule, an antisense molecule, a ribozyme, an aptamer and/or a small molecule antagonist.  
     
     
         64 . The method of  claim 63 , wherein the mammal has a disease, condition or disorder selected from the group consisting of: age-related macular degeneration, choroidal neovascularization, sickle cell retinopathy, retina vein occlusion, diabetic retinopathy, a condition associated with limbal injury, a condition associated with increased neovascularization, traumatic alkali injury, Stevens Johnson syndrome and ocular cicatricial pemphagoid.  
     
     
         65 . The method of  claim 63 , wherein the neovascularization is reduced in the cornea, the retina or the choroid.  
     
     
         66 . A method of treating or preventing neovascularization in a mammal, comprising administering to the mammal a CD18 antagonist, wherein neovascularization is reduced.  
     
     
         67 . The method of  claim 66 , wherein the CD18 antagonist is an antibody, an antibody fragment, a peptide mimetic molecule, an antisense molecule, a ribozyme, an aptamer and/or a small molecule antagonist.  
     
     
         68 . The method of  claim 67 , wherein the mammal has a disease, condition or disorder selected from the group consisting of: age-related macular degeneration, choroidal neovascularization, sickle cell retinopathy, retina vein occlusion, diabetic retinopathy, a condition associated with limbal injury, a condition associated with increased neovascularization, traumatic alkali injury, Steven's Johnson syndrome and ocular cicatricial pemphagoid.  
     
     
         69 . The method of  claim 68 , wherein the neovascularization is reduced in the cornea, the retina or the choroid.