REVERSIR™ compounds
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsVasant Jadhav, John Maraganore, Martin Maier, Kallanthottathil G. Rajeev, Muthiah Manoharan, Akin Akinc, Ivan Zlatev
Life of this patent
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Abstract
The present invention relates, in general to agents that modulate the pharmacological activity of conjugated siRNAs.
Claims25
A modified oligonucleotide consisting of 6 to 20 linked nucleotides and having a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of antisense strand of a siRNA, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strand hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand, wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are:
- (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end;
- or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).
A method of inhibiting the activity of a siRNA in a cell comprising contacting the cell with a modified oligonucleotide, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence;
- and,
- the modified oligonucleotide consists of 6 to 25 linked nucleotides and has a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand,
- wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and
- wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are:
- (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end;
- or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).
A method of treating a subject comprising:
- administering to the subject a siRNA, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence;
- monitoring the subject for siRNA activity;
- if the siRNA activity becomes higher than desired, administering a modified oligonucleotide to the subject, wherein the modified oligonucleotide consists of 6 to 25 linked nucleotides and having a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand, wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are:
- (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end;
- or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).
A method of inhibiting the activity of a siRNA in a cell comprising contacting the cell with a modified oligonucleotide, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence, wherein the modified oligonucleotide consists of 6 to 25 linked nucleotides and has a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide comprises only 2, 3, 4 or 5 locked nucleic acid (LNA) modifications, and wherein two of the LNA modifications in the modified oligonucleotide are:
- (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end;
- or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).
Dependencies are inferred from the claim text.