Modulators of pharmacological agents

Abstract

The biological activity of nucleic acid ligand is regulated (i.e. enhanced or inhibited) in vivo to produce a desired biological effect. This is accomplished through the administration of a modulator, or regulator, that changes the binding of the nucleic acid ligand for its target or that degrades or otherwise cleaves, metabolizes or breaks down the nucleic acid ligand while the ligand is still exerting its effect. Modulators of the present invention can be administered in real time as needed based on various factors, including the progress of the patient, as well as the physician's discretion in how to achieve optimal therapy. Thus, this invention provides for the first time a regulatable therapeutic regime in the course of nucleic acid ligand therapy.

1 - 51 . (canceled) 
     
     
         52 . A method of altering the affinity of a nucleic acid ligand for a target molecule in a patient comprising administering to a patient receiving said nucleic acid ligand a modulator that binds to said nucleic acid ligand, said administration being effected under conditions such that said modulator binds to said nucleic acid ligand and thereby alters the affinity of said nucleic acid ligand for said target molecule. 
     
     
         53 . The method according to claim  1  wherein upon binding of said modulator to said nucleic acid ligand, the affinity of said nucleic acid ligand for said target molecule is reduced or enhanced. 
     
     
         55 . The method according to claim  1  wherein said modulator binds to free nucleic acid ligand present in said patient. 
     
     
         56 . The method according to claim  1  wherein said modulator binds to nucleic acid ligand present in said patient in association with said target molecule. 
     
     
         57 . The method according to claim  1  wherein said modulator is an oligonucleotide complementary to said nucleic acid ligand, a nucleic acid binding peptide, polypeptide or protein, or a nucleic acid binding oligosaccharide. 
     
     
         58 . The method according to  claim 57  wherein said modulator is said oligonucleotide. 
     
     
         59 . The method according to  claim 58  wherein said oligonucleotide comprises a sequence complementary to 6-25 nucleotides of said nucleic acid ligand. 
     
     
         60 . The method according to  claim 58  wherein said oligonucleotide comprises 5-80 nucleotides. 
     
     
         61 . The method according to  claim 58  wherein said oligonucleotide bears a chemical substitution. 
     
     
         62 . The method according to  claim 61  wherein said oligonucleotide comprises a pyrimidine substituted at the 5 position or a sugar substituted at the 2′ position. 
     
     
         63 . The method according to  claim 62  wherein said oligonucleotide comprises a 2′-amino, 2′-fluoro or 2′-O-methyl substitution. 
     
     
         64 . The method according to claim  1  wherein the target is selected from interleukin, CTLA4, a growth factor, neurotransmitter receptor, or E2F family member. 
     
     
         65 . The method according to  claim 62  wherein said nucleic acid ligand and said oligonucleotide comprise D-nucleotides. 
     
     
         66 . The method according to  claim 62  wherein said oligonucleotide is produced in said patient following administration to said patient of a construct comprising a sequence encoding said oligonucleotide. 
     
     
         67 . The method according to  claim 52  wherein said nucleic acid ligand inhibits fibrin deposition or fibrin dissolution. 
     
     
         68 . The method according to  claim 52  wherein said nucleic acid ligand is an anticoagulant or antithrombotic nucleic acid ligand. 
     
     
         69 . The method according to  claim 52  wherein said modulator reverses the anticoagulant or antithrombotic effect of said nucleic acid ligand. 
     
     
         70 . The method according to  claim 52  wherein said target molecule is a tissue factor (TF)/factor VIIa (FVIIa), factor VIIIa (FVIIIa)/factor IXa (FIXa), factor Va (F Va)/factor Xa (FXa) enzyme complex, gpIIbIIIa, gpIbIX, gpVI, Gas6, PAI-1 (plasminogen activator inhibitor 1), coagulation factor XIIIa (FXIIIa), ATIII (anti-thrombin III), thrombin or coagulation factor XIa (FXIa). 
     
     
         71 . A composition comprising an oligonucleotide according to  claim 52  and a carrier. 
     
     
         72 . The composition of  claim 71  wherein the oligonucleotide has a sequence set forth in SEQ ID NO:20, 21, 22, 25-36, 38, 39, 40 or 41, or a sequence at least 95% homologous therewith.