Modified polynucleotides for reducing off-target effects in RNA interference

A functional double stranded polyribonucleotide for silencing a target gene, said double stranded polyribonucleotide comprising:

• a. a sense strand comprising a sense region, wherein said sense region comprises:
• i. a first 5′ sense nucleotide having a first 2′-O-alkyl modification;
• and
• ii. a second 5′ sense nucleotide having a second 2′-O-alkyl modification;
• and
• b. an antisense strand comprising an antisense region, wherein said antisense region comprises:
• i. a first 5′ antisense nucleotide having a third 2′-O-alkyl modification and a 5′ terminal phosphate;
• and
• ii. a second 5′ antisense nucleotide having a fourth 2′-O-alkyl modification;
• wherein said sense region and said antisense region form a duplex of 18-24 base pairs of nucleotides that has at least 80% complementarity over the range of the duplex, and within said duplex said first 5′ sense nucleotide is the 5′ most nucleotide of the sense strand, said second 5′ sense nucleotide is immediately adjacent to and downstream of the first 5′ sense nucleotide, said first 5′ antisense nucleotide is the 5′ most nucleotide of the antisense strand and said second 5′ antisense nucleotide is immediately adjacent to and downstream of the first 5′ antisense nucleotide, wherein all nucleotides of each strand of said double stranded polyribonucleotide other than said first 5′ sense nucleotide, said second 5′ sense nucleotide, said first 5′ antisense nucleotide, and said second 5′ antisense nucleotide comprises a 2′-OH, and wherein said double stranded polyribonucleotide is capable of silencing a target gene with reduced off-target gene silencing.