METHODS OF TREATING ISCHEMIA-REPERFUSION INJURY WITH siRNAS

Abstract

The disclosure relates to compounds, in particular siRNAs that inhibit the expression of specific human genes, for treating ocular diseases or disorders. The invention also relates to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The present disclosure also provides methods of treating and/or preventing the incidence or severity of various ocular diseases or disorders associated with the genes associated with such diseases or disorders by administering to a subject in need of treatment for such disease or disorder the compounds or pharmaceutical compositions in a therapeutically effective dose.

1 - 25 . (canceled) 
     
     
         26 . A method of treating an ocular disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective dose of a double-stranded ribonucleic acid (RNA) compound comprising the structure: 
       
         
           
                 
               
                   (SEQ ID NO: 140) 
                 
                 
                 
               
                     
                   5′ AGGAGUUCCACAUUCUGGC-Z 3′ (antisense strand) 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 139) 
                 
                 
                 
               
                     
                   3′ Z′-UCCUCAAGGUGUAAGACCG 5′ (sense strand); 
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         wherein each A, C, G, and U is a ribonucleotide which may be modified or unmodified in its sugar residue and wherein each consecutive ribonucleotide is joined to the next ribonucleotide by a covalent bond; and 
         wherein each of Z and Z′ may be present or absent, but if present is 1 to 5 consecutive nucleotides covalently attached at the 3′ terminus of the strand in which it is present; 
         or a pharmaceutically acceptable salt of the double-stranded RNA compound. 
       
     
     
         27 . The method of  claim 26 , wherein the therapeutically effective dose comprises an amount of the double-stranded RNA compound effective to down-regulate expression of a caspase 2, apoptosis-related cysteine peptidase (CASP-2) gene. 
     
     
         28 . The method of  claim 27 , wherein expression of the CASP-2 gene is down-regulated at least 20 percent. 
     
     
         29 . The method of  claim 26 , wherein the covalent bond joining each consecutive ribonucleotide is a phosphodiester bond. 
     
     
         30 . The method of  claim 26 , wherein at least one ribonucleotide comprises a modification in its sugar residue. 
     
     
         31 . The method of  claim 30 , wherein the modification comprises a modification at the 2′ position, said modification preferably comprising the presence of an amino, a fluoro, an alkoxy, or an alkyl group. 
     
     
         32 . The method of  claim 31 , wherein the modification comprises the presence of an alkoxy group which is a methoxy (2′-O-methyl) group. 
     
     
         33 . The method of  claim 26 , wherein alternating ribonucleotides in the antisense strand, the sense strand, or both the sense and antisense strands are modified in their sugar residues. 
     
     
         34 . The method of  claim 33 , wherein each ribonucleotide at the 5′ and 3′ termini of the antisense strand is modified in its sugar residue, and each ribonucleotide at the 5′ and 3′ termini of the sense strand is unmodified in its sugar residue. 
     
     
         35 . The method of  claim 26 , wherein both the antisense strand and the sense strand are non-phosphorylated at their 3′ termini and 5′ termini. 
     
     
         36 . The method of  claim 26 , wherein both the antisense strand and the sense strand are phosphorylated at their 3′ termini. 
     
     
         37 . The method of  claim 26 , wherein both Z and Z′ are absent. 
     
     
         38 . The method of  claim 26 , wherein one or both of Z and Z′ are present. 
     
     
         39 . The method of  claim 26 , wherein a 2′-O-methyl group is present on the first, third, fifth, seventh, ninth, eleventh, thirteenth, fifteenth, seventeenth, and nineteenth nucleotide of the antisense strand, and wherein a 2′-O-methyl group is present on the second, fourth, sixth, eighth, tenth, twelfth, fourteenth, sixteenth and eighteenth nucleotide of the sense strand. 
     
     
         40 . The method of  claim 26 , wherein the double-stranded RNA compound is combined with a pharmaceutically acceptable carrier. 
     
     
         41 . The method of  claim 26 , wherein the ocular disease or disorder comprises glaucoma. 
     
     
         42 . The method of  claim 26 , wherein the ocular disease or disorder comprises a retinal disorder. 
     
     
         43 . The method of  claim 42 , wherein the retinal disorder comprises age-related macular degeneration (AMD). 
     
     
         44 . The method of  claim 26 , wherein the retinal disorder comprises retinal pericyte apoptosis or retinal damage resulting from ischemia, or diabetic retinopathy. 
     
     
         45 . The method of  claim 26 , wherein the retinal disorder comprises dry eye syndrome. 
     
     
         46 . The method of  claim 26 , wherein the administration comprises an intraocular injection. 
     
     
         47 . The method of  claim 46 , wherein the administration comprises an intravitreal (IVT) injection. 
     
     
         48 . A double-stranded ribonucleic acid (dsRNA) compound that down-regulates CASP2 expression, wherein the double-stranded RNA compound has the structure: 
       
         
           
                 
               
                   (SEQ ID NO: 140) 
                 
                 
                 
               
                     
                   5′ AGGAGUUCCACAUUCUGGC-Z 3′ (antisense strand) 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 139) 
                 
                 
                 
               
                     
                   3′ Z′-UCCUCAAGGUGUAAGACCG 5′ (sense strand); 
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         wherein each A, C, G, and U is a ribonucleotide which may be modified or unmodified in its sugar residue and wherein each consecutive ribonucleotide is joined to the next ribonucleotide by a covalent bond; and 
         wherein each of Z and Z′ may be present or absent, but if present is 1 to 5 consecutive nucleotides covalently attached at the 3′ terminus of the strand in which it is present; 
         or a pharmaceutically acceptable salt of the double-stranded RNA compound. 
       
     
     
         49 . The dsRNA compound of  claim 48 , wherein the compound is formulated as a liquid contained in a syringe suitable for an intravitreal (IVT) injection. 
     
     
         50 . The dsRNA compound of  claim 48 , in the form of a pharmaceutically acceptable salt.