Ligand-Modified Oligonucleotides
AssigneeDicerna Pharmaceuticals, Inc.
InventorsBOB D. BROWN, WEIMIN WANG
Life of this patent
Estimating the term…
Abstract
The invention provides for double stranded nucleic acid molecules comprising a 5′extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.
Claims21
1-89. (canceled)
A double stranded nucleic acid (dsNA) comprising:
- a) a sense strand having a length of 36 nucleotides;
- b) an antisense strand having a length of 22 nucleotides;
- c) a duplex formed by the sense strand and the antisense strand, the duplex comprising 20 base pairs;
- and
- d) a single-stranded 3′-overhang of 2 nucleotides on the antisense strand;
- wherein the sense strand and antisense strands are separate strands;
- wherein the sense strand comprises a stem and a RNA tetraloop, wherein the stem has a length of 6 base pairs and three or four of the nucleotides of the RNA tetraloop are conjugated to a ligand through a 2′-hydroxyl group on a ribose of the nucleotide via a linker;
- wherein the antisense strand is sufficiently complementary to a target mRNA along at least 15 nucleotides of the antisense strand to reduce target gene expression when the double stranded nucleic acid is introduced into a mammal or a mammalian cell;
- and
- wherein the RNA tetraloop is a GNRA tetraloop, where N is adenine, G is guanine, R is adenine or guanine, and A is adenine.
A double stranded nucleic acid (dsNA) comprising:
- a) a sense strand having a length of 36 nucleotides;
- b) an antisense strand having a length of 22 nucleotides;
- c) a duplex formed by the sense strand and the antisense strand, the duplex comprising 20 base pairs;
- and
- d) a single-stranded 3′-overhang of 2 nucleotides on the antisense strand;
- wherein the sense strand and antisense strands are separate strands;
- wherein the sense strand comprises a stem and an RNA tetraloop, wherein the stem has a length of 6 base pairs;
- wherein N-acetylgalactosamine is conjugated to a sugar of three or four of the nucleotides of the RNA tetraloop via a linker as set forth in Formula VII:
- wherein B is a nucleobase, X is N-acetylgalactosamine, and m and n each independently range from 1 to 20;
- wherein the antisense strand is sufficiently complementary to a target mRNA along at least 15 nucleotides of the antisense strand to reduce target gene expression when the double stranded nucleic acid is introduced into a mammal or a mammalian cell;
- and
- wherein the RNA tetraloop consists of a GAAA sequence.
Dependencies are inferred from the claim text.