Novel siRNAS and methods of use thereof

Abstract

The invention relates to compounds, in particular siRNAs, which inhibit the expression of specific human genes. The invention also relates to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The present invention also provides a method of treating and/or preventing the incidence or severity of various diseases or conditions associated with the genes and/or symptoms associated with such diseases or conditions comprising administering to a subject in need of treatment for such disease or condition and/or symptom the compound or the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the subject. The invention also provides antibodies which inhibit specified human polypeptides and pharmaceutical compositions comprising one or more such antibodies.

1 . A compound having the structure:
   5′ (N) x -Z 3′ (antisense strand)     3′ Z′-(N′) y  5′ (sense strand)   wherein each of N and N′ is a ribonucleotide which may be modified or unmodified in its sugar residue;   wherein each of (N) x  and (N′) y  is an oligomer in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;   wherein each of x and y is an integer between 19 and 40;   wherein each of Z and Z′ may be present or absent, but if present is 1-5 consecutive nucleotides covalently attached at the 3′ terminus of the strand in which it is present; and   wherein the sequence of (N′) y  is present within an mRNA whose sequence is set forth in one of SEQ ID NO:46, SEQ ID NO:1-41 or SEQ ID NO:47-48.   
     
     
         2 . The compound of  claim 1 , wherein the covalent bond joining each consecutive N or N′ is a phosphodiester bond. 
     
     
         3 . The compound of  claim 1 , wherein x=y. 
     
     
         4 . The compound of  claim 3 , wherein each of x and y is 19, 21 or 23. 
     
     
         5 . The compound of  claim 1 , wherein Z and Z′ are absent. 
     
     
         6 . The compound of  claim 1 , wherein one of Z or Z′ is present. 
     
     
         7 . The compound of  claim 1 , wherein each of N or N′ is unmodified in its sugar residue. 
     
     
         8 . The compound of  claim 1 , wherein at least one N or N′ comprises a modification in its sugar residue. 
     
     
         9 . The compound of  claim 8 , wherein the modification comprises a modification at the 2′ position. 
     
     
         10 . The compound of  claim 9 , wherein the modification at the 2′ position comprises the presence of an amino, a fluoro, an alkoxy or an alkyl group. 
     
     
         11 . The compound of  claim 10  wherein the modification comprises the presence of an alkoxy group. 
     
     
         12 . The compound of  claim 11 , wherein the alkoxy group is methoxy (2′-O-methyl) group. 
     
     
         13 . The compound of  claim 1 , wherein alternating ribonucleotides in (N) x  are modified and alternating ribonucleotides in (N′) y  are modified. 
     
     
         14 . The compound of  claim 13 , wherein each N at the 5′ and 3′ termini in (N) x  are modified in their sugar residues, and each N′ at the 5′ and 3′ termini of (N′) y  are unmodified in their sugar residues. 
     
     
         15 . The compound of  claim 14 , wherein both (N) x  and the (N′) y  are non-phosphorylated at both their 3′ and 5′ termini or wherein both (N) x  and (N′) y  are phosphorylated at the 3′ termini. 
     
     
         16 . A compound having the structure:
   5′ (N) x -Z 3′ (antisense strand)     3′ Z′-(N′) y  5′ (sense strand)   wherein each of N and N′ is a ribonucleotide which may be modified or unmodified in its sugar residue;   wherein each of (N) x  and (N′) y  is an oligomer in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;   wherein each of x and y is an integer between 19 and 40;   wherein each of Z and Z′ may be present or absent, but if present is 1-5 consecutive nucleotides covalently attached at the 3′ terminus of the strand in which it is present; and   wherein each of (N) x  and (N′) y  is set forth in any one of SEQ ID NOS: 97 to 68654.   
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  or a vector capable of expressing such a compound in an amount effective to inhibit the gene, and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating a disease or condition selected from hearing loss, acute renal failure, glaucoma, acute respiratory distress syndrome, an acute lung injury, organ transplantation rejection, ischemia-reperfusion injury, nephrotoxicity, neurotoxicity, spinal cord injury, pressure sores, osteoarthritis, dry eye and chronic obstructive pulmonary disease (COPD), in a subject in need thereof, comprising administering to the subject an oligonucleotide which inhibits expression of a gene whose mRNA sequence is set forth in any one of SEQ ID NOS:1-41 or 46-48 in an amount effective to treat the disease or condition. 
     
     
         19 . The method according to  claim 18  wherein the oligonucleotide is siRNA. 
     
     
         20 . The method according to  claim 19  wherein the siRNA comprises an oligomer whose sequence is set forth in any one of SEQ ID NOS: 277 to 50970 and 50993-68654 (Table B). 
     
     
         21 . The method according to  claim 20  wherein the siRNA comprises an oligomer whose sequence is set forth in any one of SEQ ID NOS: 97-276 (Tables C1, C2) and SEQ ID NOS: 50971-50992 (Table C3). 
     
     
         22 . A method of treating acute renal failure in a subject in need thereof, comprising administering to the subject an oligonucleotide which inhibits expression of any one of TP53BP (whose mRNA sequence is set forth in SEQ ID NOS:1-2); LRDD (whose mRNA sequence is set forth in SEQ ID NO:3-5); CYBA (whose mRNA sequence is set forth in SEQ ID NO:6), CASP2 (whose mRNA sequence is set forth in SEQ ID NO:10-11), BNIP3 (whose mRNA sequence is set forth in SEQ ID NO:15), or Rac1 (whose mRNA sequence is set forth in SEQ ID NO:24-26) in an amount effective to treat the acute renal failure. 
     
     
         23 . A method of treating spinal-cord injury in a subject in need thereof, comprising administering to the subject an oligonucleotide which inhibits expression of any one of RHOA (whose mRNA sequence is set forth in SEQ ID NO:46); TP53BP (whose mRNA sequence is set forth in SEQ ID NOS:1-2); LRDD (whose mRNA sequence is set forth in SEQ ID NO:3-5); CYBA (whose mRNA sequence is set forth in SEQ ID NO:6), CASP2 (whose mRNA sequence is set forth in SEQ ID NO:10-11), BNIP3 (whose mRNA sequence is set forth in SEQ ID NO:15), Rac1(whose mRNA sequence is set forth in SEQ ID NO:24-26, CD38 (whose mRNA sequence is set forth in SEQ ID NO:32) or BMP2 (whose mRNA sequence is set forth in SEQ ID NO:34) in an amount effective to treat the spinal cord injury. 
     
     
         24 . A method of treating a disease or condition selected from hearing loss, acute renal failure, glaucoma, acute respiratory distress syndrome, an acute lung injury, organ transplantation rejection, ischemia-reperfusion injury, nephrotoxicity, neurotoxicity, spinal cord injury, pressure sores, osteoarthritis and chronic obstructive pulmonary disease (COPD), in a subject in need thereof, comprising administering to the subject an antibody which inhibits a polypeptide whose sequence is set forth in any one of SEQ ID NOS: 90-93 in an amount effective to treat the disease or condition. 
     
     
         25 . A pharmaceutical composition comprising an antibody which inhibits a polypeptide whose sequence is set forth in any one of SEQ ID NOS: 90-93, in an amount effective to inhibit the polypeptide, and a pharmaceutically acceptable carrier.