Small molecules that enhance the activity of oligonucleotides
Methods of administering an oligonucleotide of interest into a cell in vitro or in vivo are described. In the methods, a small organic compound active agent is concurrently administered to the cell in an amount effective to increase the delivery of the oligonucleotide into the cell, and/or increase the activity of said oligonucleotide in the cell. Compositions useful for carrying out the method are also described.
1. A method of administering an oligonucleotide of interest to a cell, the method comprising:
concurrently administering an active agent to said cell in an amount effective to increase the delivery and/or increase the activity of said oligonucleotide in said cell;
wherein said active agent is a compound of Formula I:
wherein:
R is ethyl or a linking group;
R 1 is methyl or a linking group;
R 2 is methyl;
R 3 and R 4 are each independently H, lower alkyl; lower alkoxy, halo, amino, aryl, or heteroaryl;
or a pharmaceutically acceptable salt thereof; and
wherein the oligonucleotide is not targeted to a bacterial pathogen.
2. The method of claim 1 , wherein said cell is a mammalian cell.
3. The method of claim 1 , wherein said method is carried out in vitro or in vivo.
4. The method of claim 1 , wherein said method is carried out by administering said oligonucleotide to a subject in need thereof, and concurrently administering said active agent to said subject.
5. The method of claim 1 , wherein said active agent is administered after said oligonucleotide.
6. The method of claim 1 , wherein said oligonucleotide is single stranded.
7. The method of claim 1 , wherein said oligonucleotide is from 2, 4, 6 or 8 to 100 or 200 nucleotides in length.
8. The method of claim 1 , wherein said oligonucleotide is negatively charged.
9. The method of claim 1 , wherein said oligonucleotide is an antisense oligonucleotide.
10. The method of claim 1 , wherein said oligonucleotide is a splice switching oligonucleotide.
11. The method of claim 1 , wherein said active agent is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
12. A composition comprising:
(a) an oligonucleotide and;
(b) an active agent, in combination in
(c) a pharmaceutically acceptable carrier;
wherein said active agent is a compound of Formula:
wherein:
R is ethyl or a linking group;
R 1 is methyl or a linking group;
R 2 is methyl;
R 3 and R 4 are each independently H, lower alkyl; lower alkoxy, halo, amino, aryl, or heteroaryl;
or a pharmaceutically acceptable salt thereof; and
wherein the olignucleotide is not targeted to a bacterial pathogen.
13. The composition of claim 12 , wherein said oligonucleotide is single stranded.
14. The composition of claim 12 , wherein said oligonucleotide is from 2, 4, 6 or 8 to 100 or 200 nucleotides in length.
15. The composition of claim 12 , wherein said oligonucleotide is negatively charged.
16. The composition of claim 12 , wherein said oligonucleotide is an antisense oligonucleotide.
17. The composition of claim 12 , wherein said oligonucleotide is a splice switching oligonucleotide.
18. The composition of claim 12 , wherein said active agent is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
19. A composition comprising:
(a) an oligonucleotide and;
(b) an active agent, in combination in
(c) a pharmaceutically acceptable carrier;
wherein said active agent is selected from the group consisting of:
and pharmaceutically acceptable salts thereof; and
wherein the oligonucleotide is not targeted to a bacterial pathogen.
20. A method of administering an oligonucleotide of interest to a cell, the method comprising:
concurrently administering an active agent to said cell in an amount effective to increase the delivery and/or increase the activity of said oligonucleotide in said cell;
wherein said active agent is selected from the group consisting of:
and pharmaceutically acceptable salts thereof; and
wherein the oligonucleotide is not targeted to a bacterial pathogen.