Method of modulating the activity of a nucleic acid molecule
The present invention relates, in general, to agents that modulate the pharmacological activity of nucleic acid molecules and, in particular, to agents that bind therapeutic or diagnostic nucleic acid molecules in a sequence independent manner and modulate (e.g., inhibit or reverse) their activity. The invention also relates to compositions comprising such agents and to methods of using same.
1. A method of inhibiting the activity of a nucleic acid molecule (NAM) that binds to a target molecule and elicits a pharmacological effect, said method comprising contacting said NAM with a universal antidote (UA) under conditions such that said UA binds to said NAM and modifies the interaction between said NAM and said target, wherein said binding of said UA to said NAM is independent of the nucleotide sequence of said NAM and wherein said UA is a pharmaceutically acceptable polycationic polymer selected from the group consisting of PPA-DPA, CDP, CDP-Im, PAMAM, and HDMB.
2. The method according to claim 1 wherein said NAM is an aptamer, a siRNA, a microRNA, a ribozyme or an antagomir.
3. The method according to claim 2 wherein said NAM is an aptamer.
4. The method according to claim 3 wherein said NAM is an aptamer to human factor IXa or human factor Xa.
5. The method according to claim 1 wherein said target molecule is a peptide, protein, glycoprotein, polysaccharide or nucleic acid.
6. The method according to claim 5 wherein said target molecule is an enzyme, hormone, receptor, adhesion molecule, metabolite, or cofactor.
7. The method according to claim 5 wherein said target molecule is factor VIIa, factor IXa, factor Xa, factor XIa, thrombin or protein C.
8. The method according to claim 1 wherein said UA reverses an immune system activating effect of said NAM.
9. The method according to claim 1 , wherein said UA reverses an anticoagulant and antithrombic effect of said NAM.
10. The method according to claim 1 , wherein said UA reverses an immunosuppressive effect of said NAM.
11. The method according to claim 1 , wherein said UA reverses an acetylcholine receptor blocking activity of said NAM.
12. The method according to claim 1 wherein said contacting is effected in vivo.
13. The method according to claim 12 wherein said contacting is effected in a mammal.
14. The method according to claim 13 wherein said mammal is a human.
15. A method of screening for a candidate UA capable of inhibiting the activity of a nucleic acid molecule (NAM) comprising contacting a test compound with a NAM and determining whether said test compound binds to said NAM, wherein a test compound that binds to said NAM in a manner independent of the nucleotide sequence of said NAM is a candidate UA, and wherein said UA binds said NAM with a binding constant greater than 1.0×10 6 M −1 .
16. The method according to claim 15 wherein said NAM is an aptamer.
17. The method according to claim 15 wherein said method comprises contacting a test compound with a first NAM and determining if said test compound binds to said first NAM, wherein a test compound that binds to said first NAM is then contacted with a second NAM having a sequence different from that of said first NAM and determining whether said test compound binds to said second NAM, wherein a test compound that binds to said first NAM and said second NAM is a candidate UA.
18. A method of inhibiting the activity of a nucleic acid molecule (NAM) that binds to a target molecule and elicits a pharmacological effect, said method comprising contacting said NAM with a universal antidote (UA) under conditions such that said UA binds to said NAM and modifies the interaction between said NAM and said target, wherein said binding of said UA to said NAM is independent of the nucleotide sequence of said NAM, wherein said UA is a pharmaceutically acceptable positively charged protein, lipid, or natural synthetic polymer, or pharmaceutically acceptable salt thereof selected from the group consisting of poly-L-lysine and polycationic polymers, and wherein said UA binds said NAM with a binding constant greater than 1.0×10 6 M −1 .
19. The method according to claim 18 , wherein said NAM is an aptamer.
20. The method according to claim 18 , wherein said target molecule is factor VIIa, factor IXa, factor Xa, factor XIa, thrombin or protein C.