Methods and compositions for preventing ischemia reperfusion injury in organs

Abstract

The invention, in some embodiments, relates to compounds and methods for the prevention of ischemia reperfusion injury (IRI) in organs, and in particular to IRI in organs aged 35 years and older. Specific uses include prevention of IRI in native organs in vivo, in reimplantations and in transplantations of donor organs aged 35 years and older. Additional embodiments include the prophylaxis of delayed graft function (DGF) and reduction in the frequency, amount and duration of dialysis in recipients of deceased donor kidney transplantations. The methods entail contacting the organ in vivo or ex vivo with a temporary p53 inhibitor. Novel temporary dsNA p53 inhibitors are further provided.

1 - 65 . (canceled) 
     
     
         66 . A method of prophylaxis of ischemic reperfusion injury (IRI) in a kidney at risk of IRI to inhibit acute kidney injury (AKI) in a subject at risk of IRI, the method comprising administering to the subject a temporary inhibitor of a p53 gene in an amount effective to provide prophylaxis of AKI in the subject,
 wherein the subject is aged 35 years or older; and   wherein the inhibitor is a synthetic small interfering ribonucleic acid (siRNA) having the structure:   
       
         
           
                 
                 
               
                     
                   (antisense strand) 
                 
                     
                   (SEQ ID NO: 37) 
                 
                     
                   5′ UGAAGGGUGAAAUAUUCUC 3′  
                 
                     
                     
                 
                     
                   (sense strand) 
                 
                     
                   (SEQ ID NO: 36) 
                 
                     
                   3′ ACUUCCCACUUUAUAAGAG 5′  
                 
             
                
                
                
                
                
                
                
               
            
           
         
         
           wherein each of A, C, U, and G is a ribonucleotide and each consecutive ribonucleotide is joined to the next ribonucleotide by a covalent bond; and 
           wherein alternating ribonucleotides in both the antisense strand and the sense strand are 2′-O-methyl sugar modified ribonucleotides and a 2′-O-methyl sugar modified ribonucleotide is present at both the 5′ terminus and the 3′ terminus of the antisense strand and an unmodified ribonucleotide is present at both the 5′ terminus and the 3′ terminus of the sense strand; 
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         67 . The method of  claim 66 , wherein the subject is aged 45 years or older. 
     
     
         68 . The method of  claim 66 , wherein the subject has had any one or more of cardiovascular surgery, cardiopulmonary surgery, and renal surgery. 
     
     
         69 . The method of  claim 67 , wherein the subject has had any one or more of cardiovascular surgery, cardiopulmonary surgery, and renal surgery. 
     
     
         70 . The method of  claim 66 , wherein the subject has had cardiovascular surgery. 
     
     
         71 . The method of  claim 66 , wherein the 5′ termini and the 3′ termini are unphosphorylated. 
     
     
         72 . The method of  claim 66 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         73 . The method  claim 66 , wherein the temporary inhibitor of a p53 gene is administered to the subject at a dose of about 1 to about 50 mg/kg. 
     
     
         74 . The method of  claim 66 , wherein the temporary inhibitor of a p53 gene is administered to the subject at a dose of about 10 mg/kg. 
     
     
         75 . The method of  claim 66 , wherein the temporary inhibitor is administered to the subject by intravenous (IV) injection. 
     
     
         76 . The method of  claim 75 , wherein the intravenous (IV) injection is administered to the subject in a single treatment, wherein the single treatment comprises a single dose or multiple doses. 
     
     
         77 . The method of  claim 76 , wherein the single treatment is a single intravenous push (IVP). 
     
     
         78 . The method of  claim 75 , wherein the intravenous (IV) injection is administered to the subject directly into a proximal port of a central venous line or through a peripheral line. 
     
     
         79 . The method of  claim 66 , wherein the temporary inhibitor is conjugated or formulated in liposomes or nanoparticles. 
     
     
         80 . The method of  claim 66 , wherein the subject is further administered a medication selected from the group consisting of an antiviral agent, an antifungal agent, an antimicrobial agent, and any combination thereof.