Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals
First Claim
1. A method of preferentially targeting a biologically active antisense oligonucleotide to hepatic tissues in a mammal to modulate the expression of a gene in the liver of a mammal, comprising the step of conjugating the oligonucleotide to a cholesteryl moiety and administering the cholesterol-oligonucleotide conjugate to said mammal to achieve said preferential targeting.
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Abstract
The invention is directed to oligonucleotides and oligonucleosides functionalized to include lipophilic moieties and having improved biostability and altered biodistribution in mammals. In one embodiment, such lipophilic oligonucleotide conjugates are used in a method of targeting antisense oligonucleotides to hepatic tissues and thereby preferentially modulating gene expression in the liver and associated tissues of a mammal.
114 Citations
7 Claims
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1. A method of preferentially targeting a biologically active antisense oligonucleotide to hepatic tissues in a mammal to modulate the expression of a gene in the liver of a mammal, comprising the step of conjugating the oligonucleotide to a cholesteryl moiety and administering the cholesterol-oligonucleotide conjugate to said mammal to achieve said preferential targeting.
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2. A method of modulating the expression of a nucleic acid in the hepatic system of a mammal, comprising the step of administering to said mammal a compound to modulate the expression of said nucleic acid, said compound comprising a plurality of linked nucleosides, wherein:
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each nucleoside includes a ribofuranosyl sugar portion and a base portion; and
at least one of said nucleosides bears at a 2′
-O-position, a 3′
-O-position, or a 5′
-O-position a substituent having formula;
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- 3. A method of preferentially targeting an oligonucleotide to hepatic tissues in a mammal comprising administering to said mammal an oligonucleotide having a cholesteryl moiety conjugated thereto, to preferentially target said oligonucleotide to hepatic tissues in said mammal.
Specification