Compounds and methods for modulating expression ApoB
First Claim
1. A method of modulating expression of an apolipoprotein B (ApoB) by contacting a nucleic acid encoding ApoB with a short antisense compound 10 to 14 monomers in length, comprising a 2′
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
the 2′
position of the sugar; and
wherein the short antisense compound is targeted to a nucleic acid encoding ApoB.
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Abstract
The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.
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Citations
19 Claims
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1. A method of modulating expression of an apolipoprotein B (ApoB) by contacting a nucleic acid encoding ApoB with a short antisense compound 10 to 14 monomers in length, comprising a 2′
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
the 2′
position of the sugar; and
wherein the short antisense compound is targeted to a nucleic acid encoding ApoB. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
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17. A method of inhibiting expression of ApoB RNA in an animal, comprising administering to said animal the short antisense compound 10 to 14 monomers in length, comprising a 2′
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
the 2′
position of the sugar; and
wherein the short antisense compound is targeted to a nucleic acid encoding ApoB. - View Dependent Claims (19)
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
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18. A method of treating a cardiovascular disorder in an animal, comprising administering to an animal in need of such therapy a short antisense compound 10 to 14 monomers in length, comprising a 2′
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
the 2′
position of the sugar; and
wherein the short antisense compound is targeted to a nucleic acid encoding ApoB.
- -deoxyribonucleotide gap region flanked on each side by at least one wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, which are sugar-modified nucleotides that comprise a bridge between the 4′ and
Specification