Modified polynucleotides for reducing off-target effects in RNA interference
First Claim
Patent Images
1. A double stranded ribonucleotide comprising:
- a. a sense strand comprising a sense region, wherein said sense region comprises;
i. a first 5′
sense nucleotide, wherein said first 5′
sense nucleotide comprises a first 2′
-O-alkyl modification, and ii. a second 5′
sense nucleotide, wherein said second 5′
sense nucleotide comprises 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, wherein said first 5′
antisense nucleotide is phosphorylated, and ii. a second 5′
antisense nucleotide, wherein said second 5′
antisense nucleotide comprises a third 2′
-O-alkyl modification, wherein said sense region and said antisense region are capable of forming 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, and wherein all nucleotides other than said first 5′
sense nucleotide, said second 5′
sense nucleotide, and said second 5′
antisense nucleotide comprise a 2′
-OH.
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Abstract
Methods and compositions for performing RNA interference with decreased off-target effects are provided The methods and compositions permit effective and efficient applications of RNA interference to applications such as diagnostics and therapeutics through the use of modifications to the siRNA. Uniquely modified siRNAs have been developed that reduce off-target effects incurred in gene-silencing. The modifications comprise 2′-O-alkyl or mismatch modification(s) at specific positions on the sense and/or antisense strands.
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Citations
13 Claims
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1. A double stranded ribonucleotide comprising:
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a. a sense strand comprising a sense region, wherein said sense region comprises;
i. a first 5′
sense nucleotide, wherein said first 5′
sense nucleotide comprises a first 2′
-O-alkyl modification, andii. a second 5′
sense nucleotide, wherein said second 5′
sense nucleotide comprises 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, wherein said first 5′
antisense nucleotide is phosphorylated, andii. a second 5′
antisense nucleotide, wherein said second 5′
antisense nucleotide comprises a third 2′
-O-alkyl modification,wherein said sense region and said antisense region are capable of forming 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, and wherein all nucleotides other than said first 5′
sense nucleotide, said second 5′
sense nucleotide, and said second 5′
antisense nucleotide comprise a 2′
-OH. - View Dependent Claims (3, 8)
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11. A double stranded ribonucleotide comprising:
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a. a sense strand comprising a sense region, wherein said sense region comprises;
i. a first 5′
sense nucleotide, wherein said first 5′
sense nucleotide comprises a first 2′
-O-alkyl modification, andii. a second 5′
sense nucleotide, wherein said second 5′
sense nucleotide comprises 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, wherein said first 5′
antisense nucleotide is phosphorylated and wherein said first 5′
antisense nucleotide comprises a third 2′
-O-alkyl modification; and
ii. a second 5′
antisense nucleotide, wherein said second 5′
antisense nucleotide comprises a fourth 2′
-O-alkyl modification,wherein said sense region and said antisense region are capable of forming 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, and wherein all nucleotides other than said first 5′
sense nucleotide, said second 5′
sense nucleotide, said first 5′
antisense nucleotide, and said second 5′
antisense nucleotide comprise a 2′
-OH. - View Dependent Claims (12, 13)
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Specification