Modified polynucleotides for reducing off-target effects in RNA interference
First Claim
Patent Images
1. A double stranded polyribonucleotide 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, 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, wherein all nucleotides of each strand of said double stranded polyribonucleotide other than said first 5′
sense nucleotide, said second 5′
sense nucleotide, and said second 5′
antisense nucleotide comprises a 2′
-OH, and wherein said antisense strand is capable of silencing a target gene with reduced off-target gene silencing.
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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
10 Claims
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1. A double stranded polyribonucleotide 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; andb. 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, wherein all nucleotides of each strand of said double stranded polyribonucleotide other than said first 5′
sense nucleotide, said second 5′
sense nucleotide, and said second 5′
antisense nucleotide comprises a 2′
-OH, and wherein said antisense strand is capable of silencing a target gene with reduced off-target gene silencing.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. A double stranded polyribonucleotide 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-methyl modification, andii. a second 5′
sense nucleotide, wherein said second 5′
sense nucleotide comprises a second 2′
-O-methyl modification; andb. 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-methyl modification,wherein said sense region and said antisense region are capable of forming a duplex of 19 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, and said second 5′
antisense nucleotide comprises a 2′
-OH, wherein the double stranded polyribonucleotide comprises an overhang of two nucleotides at the 3′
termini of both said sense strand and said antisense strand and wherein said antisense strand is capable of silencing a target gene with reduced off-target gene silencing.- View Dependent Claims (10)
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Specification