Perfusion and/or preservation solution for organs

Abstract

The present invention relates to a solution for preservation, perfusion, and/or reperfusion of an organ, especially the heart, for transplantation. The solution contains peptide inhibitor(s) of protein kinase C βII (PKC βII) and/or of protein kinase C ζ (PKC ζ) and/or peptide activator(s) of protein kinase C δ (PKCδ). Methods for using the inventive solution are also disclosed, including methods for preserving an organ for transplantation, for protecting an ischemic organ from damage, for attenuating organ dysfunction after ischemia, for maintaining nitric oxide release and/or inhibiting superoxide release in an ischemic organ, and for protecting an organ from damage when isolated from the circulatory system.

1 . A solution for perfusion, preservation, and/or re-perfusion for organ preservation comprising at least one peptide inhibitor of protein kinase C βII (PKCβII) and/or at least one peptide inhibitor of protein kinase C ζ (PKCζ) and/or at least one peptide activator of PKC δ.  
     
     
         2 . The solution of  claim 1 , wherein the peptide inhibitors are dissolved in saline solution.  
     
     
         3 . The solution of  claim 1 , further comprising potassium chloride.  
     
     
         4 . The solution of  claim 1 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         5 . The solution of  claim 1 , wherein the at least one peptide activator of PKCδ is SEQ ID NO: 3.  
     
     
         6 . The solution of  claim 1 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         7 . The solution of  claim 1 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         8 . The solution of  claim 1 , wherein the concentration of the at least one peptide activator of PKCδ is about 5-10 μM.  
     
     
         9 . The solution of  claim 1 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         10 . The solution of  claim 1 , wherein the organ is a heart.  
     
     
         11 . The solution of  claim 1 , wherein the organ is a mammalian organ.  
     
     
         12 . The solution of  claim 11 , wherein the mammal is human.  
     
     
         13 . The solution of  claim 1 , wherein the organ is preserved for transplantation.  
     
     
         14 . The solution of  claim 1 , wherein the peptide inhibitors/activator are myristolated.  
     
     
         15 . A method for preserving an organ for transplantation comprising the step of perfusing the organ with the solution of  claim 1 .  
     
     
         16 . The method of  claim 15 , wherein the peptide inhibitors/activator are dissolved in saline solution.  
     
     
         17 . The method of  claim 15 , further comprising potassium chloride.  
     
     
         18 . The method of  claim 15 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         19 . The method of  claim 15 , wherein the at least one peptide activator of PKCδ is SEQ ID NO: 3.  
     
     
         20 . The method of  claim 15 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         21 . The method of  claim 15 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         22 . The method of  claim 15 , wherein the concentration of the at least one peptide activator of PKCδ is about 5-10 μM.  
     
     
         23 . The method of  claim 15 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         24 . The method of  claim 15 , wherein the organ is a heart.  
     
     
         25 . The method of  claim 15 , wherein the organ is a mammalian organ.  
     
     
         26 . The method of  claim 25 , wherein the mammal is human.  
     
     
         27 . The method of  claim 15 , wherein the organ is preserved for transplantation.  
     
     
         28 . The method of  claim 15 , wherein the wherein the peptide inhibitors/activators are myristolated.  
     
     
         29 . The method of  claim 15 , further comprising the step of submerging the organ in the solution of  claim 1 .  
     
     
         30 . The method of  claim 15 , wherein the perfusing step takes place at a rate of less than about 20 mL/minute.  
     
     
         31 . The method of  claim 15 , wherein the perfusing step takes place at a rate of about 1 mL/minute.  
     
     
         32 . The method of  claim 15 , wherein the perfusing step is a retrograde perfusion.  
     
     
         33 . The method of  claim 15 , wherein the perfusing step lasts about 5 minutes.  
     
     
         34 . A method for protecting an ischemic organ from damage comprising the step of perfusing the organ with the solution of  claim 1 .  
     
     
         35 . The method of  claim 34 , wherein the peptide inhibitors/activators are dissolved in saline solution.  
     
     
         36 . The method of  claim 34 , further comprising potassium chloride.  
     
     
         37 . The method of  claim 34 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         38 . The method of  claim 34 , wherein the at least one peptide activator of PKCδ is SEQ ID NO: 3.  
     
     
         39 . The method of  claim 34 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         40 . The method of  claim 34 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         41 . The method of  claim 34 , wherein the concentration of the at least one peptide activator of PKCδ is about 5-10 μM.  
     
     
         42 . The method of  claim 34 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         43 . The method of  claim 34 , wherein the organ is a heart.  
     
     
         44 . The method of  claim 34 , wherein the organ is a mammalian organ.  
     
     
         45 . The method of  claim 44 , wherein the mammal is human.  
     
     
         46 . The method of  claim 34 , wherein the organ is preserved for transplantation.  
     
     
         47 . The method of  claim 34 , wherein the wherein the peptide inhibitors/activators are myristolated.  
     
     
         48 . The method of  claim 34 , further comprising the step of submerging the organ in the solution of  claim 1 .  
     
     
         49 . The method of  claim 34 , wherein the perfusing step takes place at a rate of less than about 20 mL/minute.  
     
     
         50 . The method of  claim 34 , wherein the perfusing step takes place at a rate of about 1 mL/minute.  
     
     
         51 . The method of  claim 34 , wherein the perfusing step is a retrograde perfusion.  
     
     
         52 . The method of  claim 34 , wherein the perfusing step lasts about 5 minutes.  
     
     
         53 . A method for attenuating organ dysfunction after ischemia comprising the step of perfusing the organ with the solution of  claim 1 .  
     
     
         54 . The method of  claim 53 , wherein the peptide inhibitors/activator are dissolved in saline solution.  
     
     
         55 . The method of  claim 53 , further comprising potassium chloride.  
     
     
         56 . The method of  claim 53 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         57 . The method of  claim 53 , wherein the at least one peptide activator of PKCδ is SEQ ID NO: 3.  
     
     
         58 . The method of  claim 53 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         59 . The method of  claim 53 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         60 . The method of  claim 53 , wherein the concentration of the at least one peptide activator of PKCδ is about 5-10 μM.  
     
     
         61 . The method of  claim 53 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         62 . The method of  claim 53 , wherein the organ is a heart.  
     
     
         63 . The method of  claim 53 , wherein the organ is a mammalian organ.  
     
     
         64 . The method of  claim 63 , wherein the mammal is human.  
     
     
         65 . The method of  claim 53 , wherein the organ is preserved for transplantation.  
     
     
         66 . The method of  claim 53 , wherein the wherein the peptide inhibitors/activator are myristolated.  
     
     
         67 . The method of  claim 53 , further comprising the step of submerging the organ in the solution of  claim 1 .  
     
     
         68 . The method of  claim 53 , wherein the perfusing step takes place at a rate of less than about 20 mL/minute.  
     
     
         69 . The method of  claim 53 , wherein the perfusing step takes place at a rate of about 1 mL/minute.  
     
     
         70 . The method of  claim 53 , wherein the perfusing step is a retrograde perfusion.  
     
     
         71 . The method of  claim 53 , wherein the perfusing step lasts about 5 minutes.  
     
     
         72 . A method for maintaining nitric oxide release in an ischemic organ comprising the step of perfusing the organ with the solution of  claim 1 .  
     
     
         73 . The method of  claim 72 , wherein the peptide inhibitors/activator are dissolved in saline solution.  
     
     
         74 . The method of  claim 72 , further comprising potassium chloride.  
     
     
         75 . The method of  claim 72 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         76 . The method of  claim 72 , wherein the at least one peptide inhibitor of PKCδ is SEQ ID NO: 3.  
     
     
         77 . The method of  claim 72 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         78 . The method of  claim 72 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         79 . The method of  claim 72 , wherein the concentration of the at least one peptide activator of PKCδ is about 5-10 μM.  
     
     
         80 . The method of  claim 72 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         81 . The method of  claim 72 , wherein the organ is a heart.  
     
     
         82 . The method of  claim 72 , wherein the organ is a mammalian organ.  
     
     
         83 . The method of  claim 82 , wherein the mammal is human.  
     
     
         84 . The method of  claim 72 , wherein the organ is preserved for transplantation.  
     
     
         85 . The method of  claim 72 , wherein the wherein the peptide inhibitors/activator are myristolated.  
     
     
         86 . The method of  claim 72 , further comprising the step of submerging the organ in the solution of  claim 1 .  
     
     
         87 . The method of  claim 72 , wherein the perfusing step takes place at a rate of less than about 20 mL/minute.  
     
     
         88 . The method of  claim 72 , wherein the perfusing step takes place at a rate of about 1 mL/minute.  
     
     
         89 . The method of  claim 72 , wherein the perfusing step is a retrograde perfusion.  
     
     
         90 . The method of  claim 72 , wherein the perfusing step lasts about 5 minutes.  
     
     
         91 . A method for protecting an organ from damage after isolation from the circulatory system comprising the step of perfusing the organ with the solution of  claim 1 .  
     
     
         92 . The method of  claim 91 , wherein the peptide inhibitors/activator are dissolved in saline solution.  
     
     
         93 . The method of  claim 91 , further comprising potassium chloride.  
     
     
         94 . The method of  claim 91 , wherein the at least one peptide inhibitor of PKCβII is SEQ ID NO: 1.  
     
     
         95 . The method of  claim 91 , wherein the at least one peptide activator of PKCδ is SEQ ID NO: 3.  
     
     
         96 . The method of  claim 91 , wherein the at least one peptide inhibitor of PKCζ is selected form the group consisting of SEQ ID NO: 2 and Gö6983.  
     
     
         97 . The method of  claim 91 , wherein the concentration of the at least one peptide inhibitor of PKCβII is about 5-10 μM.  
     
     
         98 . The method of  claim 91 , wherein the concentration of the at least one peptide activator of PKC δ is about 5-10 μM.  
     
     
         99 . The method of  claim 91 , wherein the concentration of the at least one peptide inhibitor of PKCζ is about 2.5-5 μM.  
     
     
         100 . The method of  claim 91 , wherein the organ is a heart.  
     
     
         101 . The method of  claim 91 , wherein the organ is a mammalian organ.  
     
     
         102 . The method of  claim 101 , wherein the mammal is human.  
     
     
         103 . The method of  claim 91 , wherein the organ is preserved for transplantation.  
     
     
         104 . The method of  claim 91 , wherein the wherein the peptide inhibitors/activator are myristolated.  
     
     
         105 . The method of  claim 91 , further comprising the step of submerging the organ in the solution of  claim 1 .  
     
     
         106 . The method of  claim 91 , wherein the perfusing step takes place at a rate of less than about 20 mL/minute.  
     
     
         107 . The method of  claim 91 , wherein the perfusing step takes place at a rate of about 1 mL/minute.  
     
     
         108 . The method of  claim 91 , wherein the perfusing step is a retrograde perfusion.  
     
     
         109 . The method of  claim 91 , wherein the perfusing step lasts about 5 minutes.