Targeted gene correction by single-stranded oligodeoxynucleotides
First Claim
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1. A method of targeting and modifying, by mismatch repair, a pre-selected target nucleic acid, wherein a single-stranded oligonucleotide contains a mismatch to a targeted base in said pre-selected target nucleic acid, comprising:
- a) administering said single-stranded oligonucleotide to a cell;
b) base pairing of said single-stranded oligonucleotide to said pre-selected target nucleic acid; and
c) incorporating said mismatch into said target nucleic acid.
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Abstract
The present invention relates to using single-stranded oligonucleotides that are designed to specifically change a base in a target nucleic acid sequence. This alteration is maintained, expressed and regulated as the normal endogenous gene.
111 Citations
22 Claims
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1. A method of targeting and modifying, by mismatch repair, a pre-selected target nucleic acid, wherein a single-stranded oligonucleotide contains a mismatch to a targeted base in said pre-selected target nucleic acid, comprising:
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a) administering said single-stranded oligonucleotide to a cell;
b) base pairing of said single-stranded oligonucleotide to said pre-selected target nucleic acid; and
c) incorporating said mismatch into said target nucleic acid. - View Dependent Claims (2, 3, 4, 5, 6, 7)
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8. A method of treating a genetic disorder, or other condition wherein an alteration of a target DNA sequence is desired, comprising:
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a) administering to a mammal a therapeutically effective amount of an oligonucleotide;
b) base pairing of said oligonucleotide to said target DNA sequence, with the exception of a mismatch to a targeted base in said targeted DNA sequence; and
c) incorporating said mismatch into said targeted DNA sequence in a sequence-specific manner.
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9. A method of targeting and modifying, by mismatch repair, a pre-selected target nucleic acid in a stem cell, wherein a single-stranded oligonucleotide contains a mismatch to a targeted base in said pre-selected target nucleic acid, comprising:
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a) administering said single-stranded oligonucleotide to said stem cell;
b) base pairing of said single-stranded oligonucleotide to said pre-selected target nucleic acid; and
b) incorporating said mismatch into said target nucleic acid. - View Dependent Claims (10, 11)
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12.he. The method of claim 11, wherein said base modification comprises a modification at the 5-position of pyrimidines, said modification selected from the group of consisting of:
- 5-fluoro-2′
-deoxyuridine, 5-bromo-2′
-deoxyuridine and 5-methyl-2′
-deoxycytidine.
- 5-fluoro-2′
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13.he. The method of claim 11, wherein said 3′
- and/or 5′
end modification is at least one of the group of 2′
-O-methyl bases, 3′
amine groups, phosphothioates, or any modified base which is nuclease resistant.
- and/or 5′
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14.he. The method of claim 11, wherein said backbone modification is one of the group of phophorothioates, phosphoramidites, methylphosphonates, and modifications with nonphosphate internucleotide bonds, said nonphosphate internucleotide bonds selected from the group consisting of carbonates, carbamates, siloxanes, sulfonamides and polyamides.
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15. The method of claim 11, wherein said sugar modifications are chosen from the group of 2′
- -O-methyl RNA, 2′
-fluoro RNA and 2′
-methoxyethoxy RNA.
- -O-methyl RNA, 2′
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16. A method of targeting and modifying, by mismatch repair, a pre-selected target nucleic acid in a skin cell, wherein a single-stranded oligonucleotide contains a mismatch to a targeted base in said pre-selected target nucleic acid, comprising:
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a) administering said single-stranded oligonucleotide to said skin;
b) base pairing of said single-stranded oligonucleotide to said pre-selected target nucleic acid in a cell in said skin; and
b) incorporating said mismatch into said target nucleic acid. - View Dependent Claims (17, 18)
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19.he. The method of claim 18, wherein said base modification comprises a modification at the 5-position of pyrimidines, said modification selected from the group of consisting of:
- 5-fluoro-2′
-deoxyuridine, 5-bromo-2′
-deoxyuridine and 5-methyl-2′
-deoxycytidine.
- 5-fluoro-2′
-
20.he. The method of claim 18, wherein said 3′
- and/or 5′
end modification is at least one of the group of 2′
-O-methyl bases, 3′
amine groups, phosphothioates, or any modified base which is nuclease resistant.
- and/or 5′
-
21.he. The method of claim 18, wherein said backbone modification is one of the group of phophorothioates, phosphoramidites, methylphosphonates, and modifications with nonphosphate internucleotide bonds, said nonphosphate internucleotide bonds selected from the group consisting of carbonates, carbamates, siloxanes, sulfonamides and polyamides.
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22. The method of claim 18, wherein said sugar modifications are chosen from the group of 2′
- -O-methyl RNA, 2′
-fluoro RNA and 2′
-methoxyethoxy RNA.
- -O-methyl RNA, 2′
Specification