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 double-stranded siRNA 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 18 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  comprises SEQ ID NO:213 and the sequence of (N) x  comprises SEQ ID NO:214 which is complementary to SEQ ID NO:213.   
     
     
         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 both x and y are one of 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 all of the ribonucleotides in (N) x  or (N′) y  or both are unmodified in their sugar residue. 
     
     
         8 . The compound of  claim 1 , wherein at least one ribonucleotide comprises a modification in its sugar residue. 
     
     
         9 . The compound of  claim 8 , wherein the modification comprises a modification at the 2′ position of the sugar residue. 
     
     
         10 . The compound of  claim 9 , wherein the modification at the 2′ position of the sugar residue 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 a methoxy(2′-O-methyl) group. 
     
     
         13 . The compound of  claim 1 , wherein alternating ribonucleotides in (N) x  and/or (N′) y  are modified. 
     
     
         14 . The compound of  claim 13 , wherein each N at the 5′ and 3′ termini in (N) x  is modified in its sugar residue, and each N′ at the 5′ and 3′ termini of (N′) y  is unmodified in its sugar residue. 
     
     
         15 . The compound of  claim 14 , wherein (N) x  and (N′) y  are non-phosphorylated at their 3′ and 5′ termini or wherein (N) x  and (N′) y  are phosphorylated at their 3′ termini. 
     
     
         16 . A double-stranded siRNA compound the structure of which is:
 5′ UUCAAAUGAUGCAGGACUC 3′ (antisense strand; SEQ ID NO:214)   3′ AAGUUUACUACGUCCUGAG 5′ (sense strand; SEQ ID NO:213)   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.   
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  or  16 , and a pharmaceutically acceptable carrier. 
     
     
         18 - 25 . (canceled)