Duplex Oligonucleotides with Enhanced Functionality in Gene Regulation

A duplex oligonucleotide complex comprising:

• (a) a sense strand that is nineteen nucleotides in length, wherein nucleotides 1 and 2 and all C and all U nucleotides on said sense strand are 2′O-methyl modified;
• (b) an antisense strand that is twenty-one nucleotides in length, wherein
• (i) all C nucleotides and all U nucleotides on said antisense strand are 2′F modified;
• and
• (ii) the sense strand and the antisense strand form a duplex having a two nucleotide overhang at the 3′ end of the antisense strand, said two nucleotide overhang comprising phosphorothioate linkages;
• (c) a cholesterol molecule attached to the 3′ end of the sense strand via a C5 linker molecule thereby forming a cholesterol-linker-sense strand structure of:
• (d) a phosphate group at the 5′ end of the antisense strand;
• and
• (e) three mismatches on the sense strand with the corresponding nucleotides on the antisense strand, wherein the mismatches are between nucleotide 6 on the sense strand and opposite nucleotide 14 on the antisense strand, nucleotide 13 on the sense strand and opposite nucleotide 7 on the antisense strand, and nucleotide 19 on the sense strand and opposite nucleotide 1 on the antisense strand,
• wherein each nucleotide number refers to the nucleotide's position in an identified strand as counted form the identified strand's 5′ end, and at all positions other than positions 6, 13 and 19 on the sense strand, there is a nucleotide that is complementary to the nucleotide on the opposite strand.