CA2561868A1 - Modified polynucleotides for reducing off-target effects in rna interference - Google Patents
Modified polynucleotides for reducing off-target effects in rna interference Download PDFInfo
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- CA2561868A1 CA2561868A1 CA002561868A CA2561868A CA2561868A1 CA 2561868 A1 CA2561868 A1 CA 2561868A1 CA 002561868 A CA002561868 A CA 002561868A CA 2561868 A CA2561868 A CA 2561868A CA 2561868 A1 CA2561868 A1 CA 2561868A1
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- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
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- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
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- C12N2310/00—Structure or type of the nucleic acid
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- C12N2310/321—2'-O-R Modification
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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.
Claims (27)
- WHAT IS CLAIMED IS:
- 2. A double stranded ribonucleotide comprising:
i. 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 ii. 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, acid 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. - 3. The double stranded ribonucleotide of claim 1, wherein said first 5' antisense nucleotide comprises an -OH at its 2' position.
- 4. The double stranded ribonucleotide of claim 2, wherein said first 2'-O-alkyl modification comprises 2'-O-methyl, said second 2'-O-alkyl modification comprises 2'-O-methyl, and said third 2'-O-alkyl modification comprises 2'-O-methyl.
- 5. The double stranded ribonucleotide according to claim 3, further comprising a 2'-OH on all nucleotides other than said first 5' sense nucleotide, said second 5' sense nucleotide and said second 5' antisense nucleotide.
- 6. The double stranded ribonucleotide of claim 1, wherein said first 5' antisense nucleotide comprises a fourth 2'-O-alkyl modification.
- 7. The double stranded ribonucleotide of claim 5, wherein said first 2'-O-alkyl modification comprises 2'-O-methyl, said second 2'-O-alkyl modification comprises 2'-O-methyl, said third 2'-O-alkyl modification comprises 2'-O-methyl, and said fourth 2'-O-alkyl modification comprises 2'-O-methyl.
- 8. The double stranded ribonucleotide according to claim 6, further comprising a 2'-OH on all nucleotides other than on said first 5' sense nucleotide, said second 5' sense nucleotide, said first 5' antisense nucleotide, and said second 5' antisense nucleotide.
- 9. The double stranded ribonucleotide of claim 1, further comprising a 3' overhang of 1 to 6 bases on at least one of said sense strand and said antisense strand.
- 10. The double stranded ribonucleotide of claim 4, further comprising a 3' overhang of 1 to 6 bases on at least one of said sense strand and said antisense strand.
- 11. The double stranded ribonucleotide of claim 7, further comprising a 3' overhang of 1 to 6 bases on at least one of said sense strand and said antisense strand.
- 12. A kit, comprising at least two siRNA, wherein the at least two siRNA
comprise a first siRNA and a second siRNA, and wherein each of the first siRNA and the second siRNA comprises:
i. a sense strand, wherein said sense strand 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 ii. an antisense strand, wherein said antisense strand 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 strand and said antisense strand are capable of forming a duplex of 18-24 base pairs of nucleotides, wherein the duplex 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, and 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. - 13. A kit according to claim 11, wherein the first siRNA and the second siRNA
each comprises a sequence that is at least substantially complementary to a region in a target mRNA. - 14. A kit according to claim 12, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary overlaps the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
- 15. A kit according to claim 12, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary does not overlap the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
- 16. A kit, comprising at least two unimolecular siRNA, wherein the at least two siRNA comprise a first siRNA and a second siRNA, and wherein each of the first siRNA and the second siRNA comprises:
i. 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 ii. 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, wherein the duplex 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 region, and 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 region and said second 5' antisense nucleotide is immediately adjacent to and downstream of the first 5' antisense nucleotide. - 17. A kit according to claim 15, wherein the first siRNA and the second siRNA
each comprises a sequence that is at least substantially complementary to a region in a target mRNA. - 18. A kit according to claim 16, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary overlaps the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
- 19. A kit according to claim 17, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary does not overlap the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
- 20. A method for minimizing off target effects in RNAi, said method comprising:
i. exposing at least two unimolecular siRNA to a target nucleic acid or to a cell, wherein the at least two unimolecular siRNA comprise a first unimolecular siRNA and a second unimolecular siRNA, wherein each of the first unimolecular siRNA and the second unimolecular siRNA
comprises i. a sense region, wherein said sense region comprises 1. a first 5' sense nucleotide, wherein said first 5' sense nucleotide comprises a first 2'-O-alkyl modification;
and 2. a second 5' sense nucleotide, wherein said second 5' sense nucleotide comprises a second 2'-O-alkyl modification; and ii. an antisense region, wherein said antisense region comprises 1. a first 5' antisense nucleotide, wherein said first 5' antisense nucleotide is phosphorylated; and 2. 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, wherein the duplex 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 region, and 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 region and said second 5' antisense nucleotide is immediately adjacent to and downstream of the first 5' antisense nucleotide. - 21. A method according to claim 19, wherein the first unimolecular siRNA and the second unimolecular siRNA each comprises a sequence that is at least substantially complementary to a region in a target mRNA.
- 22. A method according to claim 20, wherein the region of the target mRNA to which the sequence of the first unimolecular siRNA is at least substantially complementary overlaps the region of the target mRNA to which the sequence of the second unimolecular siRNA is at least substantially complementary.
- 23. A method according to claim 20, wherein the region of the target mRNA to which the sequence of the first unimolecular siRNA is at least substantially complementary does not overlap the region of the target mRNA to which the sequence of the second unimolecular siRNA is at least substantially complementary.
- 24. A method for minimizing off target effects in RNAi, said method comprising:
i. exposing at least two siRNA to a target nucleic acid or to a cell, wherein the at least two siRNA comprise a first siRNA and a second siRNA, wherein each of the first siRNA and the second siRNA comprises a sense strand, wherein said sense strand comprises 1. a first 5' sense nucleotide, wherein said first 5' sense nucleotide comprises a first 2'-O-alkyl modification;
and 2. a second 5' sense nucleotide, wherein said second 5' sense nucleotide comprises a second 2'-O-alkyl modification; and ii. an antisense strand, wherein said antisense strand comprises 1. a first 5' antisense nucleotide, wherein said first 5' antisense nucleotide is phosphorylated; and 2. a second 5' antisense nucleotide, wherein said second 5' antisense nucleotide comprises a third 2'-O-alkyl modification;
wherein said sense strand and said antisense strand are capable of forming a duplex of 18-24 base pairs of nucleotides, wherein the duplex 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, and 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. - 25. A method according to claim 23, wherein the first siRNA and the second siRNA
each comprises a sequence that is at least substantially complementary to a region in a target mRNA. - 26. A method according to claim 24, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary overlaps the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
- 27. A method according to claim 24, wherein the region of the target mRNA to which the sequence of the first siRNA is at least substantially complementary does not overlap the region of the target mRNA to which the sequence of the second siRNA is at least substantially complementary.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2004/010343 WO2004090105A2 (en) | 2003-04-02 | 2004-04-01 | Modified polynucleotides for use in rna interference |
USPCT/US04/10343 | 2004-04-01 | ||
US63022804P | 2004-11-22 | 2004-11-22 | |
US60/630,228 | 2004-11-22 | ||
US11/019,831 | 2004-12-22 | ||
US11/019,831 US7595387B2 (en) | 2004-04-01 | 2004-12-22 | Modified polynucleotides for reducing off-target effects in RNA interference |
PCT/US2005/011008 WO2005097992A2 (en) | 2004-04-01 | 2005-03-31 | Modified polynucleotides for reducing off-target effects in rna interference |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2561868A1 true CA2561868A1 (en) | 2005-10-20 |
CA2561868C CA2561868C (en) | 2012-11-06 |
Family
ID=42470686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2561868A Active CA2561868C (en) | 2004-04-01 | 2005-03-31 | Modified polynucleotides for reducing off-target effects in rna interference |
Country Status (7)
Country | Link |
---|---|
US (5) | US20070167384A1 (en) |
EP (1) | EP1733035B1 (en) |
JP (1) | JP5112854B2 (en) |
KR (1) | KR101147147B1 (en) |
AU (1) | AU2005230850B2 (en) |
CA (1) | CA2561868C (en) |
WO (1) | WO2005097992A2 (en) |
Families Citing this family (145)
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EP1633767B1 (en) * | 2003-06-02 | 2018-11-21 | University of Massachusetts | Methods and compositions for controlling efficacy of rna silencing |
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WO2005001043A2 (en) * | 2003-06-02 | 2005-01-06 | University Of Massachusetts | METHODS AND COMPOSITIONS FOR ENHANCING THE EFFICACY AND SPECIFICITY OF FNAi |
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US20050203043A1 (en) * | 2004-01-23 | 2005-09-15 | Dharmacon, Inc. | Identification of toxic nucleotide sequences |
KR101147147B1 (en) * | 2004-04-01 | 2012-05-25 | 머크 샤프 앤드 돔 코포레이션 | Modified polynucleotides for reducing off-target effects in rna interference |
WO2005097817A2 (en) | 2004-04-05 | 2005-10-20 | Alnylam Pharmaceuticals, Inc. | Process and reagents for oligonucleotide synthesis and purification |
CA2562685C (en) | 2004-04-27 | 2013-09-17 | Alnylam Pharmaceuticals, Inc. | Single-stranded and double-stranded oligonucleotides comprising a 2-arylpropyl moiety |
US7674778B2 (en) | 2004-04-30 | 2010-03-09 | Alnylam Pharmaceuticals | Oligonucleotides comprising a conjugate group linked through a C5-modified pyrimidine |
AU2005252662B2 (en) * | 2004-06-03 | 2011-08-18 | Isis Pharmaceuticals, Inc. | Double strand compositions comprising differentially modified strands for use in gene modulation |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
EP1789553B1 (en) | 2004-06-30 | 2014-03-26 | Alnylam Pharmaceuticals Inc. | Oligonucleotides comprising a non-phosphate backbone linkage |
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2004
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AU2005230850A1 (en) | 2005-10-20 |
JP5112854B2 (en) | 2013-01-09 |
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CA2561868C (en) | 2012-11-06 |
KR101147147B1 (en) | 2012-05-25 |
US7595387B2 (en) | 2009-09-29 |
JP2007531520A (en) | 2007-11-08 |
US20070173476A1 (en) | 2007-07-26 |
US20070167384A1 (en) | 2007-07-19 |
EP1733035A2 (en) | 2006-12-20 |
EP1733035B1 (en) | 2013-08-21 |
US20100197023A1 (en) | 2010-08-05 |
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