Immunomodulatory oligonucleotides

Abstract

Oligonucleotides containing unthylated CpG dinucleotides and therapeutic utilities based on their ability to stimulate an immune response in a subject are disclosed. Also disclosed are therapies for treating diseases associated with immune system activation that are initiated by unthylated CpG dinucleotides in a subject comprising administering to the subject oligonucleotides that do not contain unmethylated CpG sequences (i.e. methylated CpG sequences or no CpG sequence) to outcompete unmethylated CpG nucleic acids for binding. Further disclosed are methylated CpG containing dinucleotides for use antisense therapies or as in vivo hybridization probes, and immunoinhibitory oligonucleotides for use as antiviral therapeutics.

1 - 36 . (canceled)  
     
     
         37 . A composition for treating an immune system deficiency comprising a vaccine and an oligonucleotide delivery complex having an immunostimulatory CpG containing oligonucleotide associated with a lipid or a sterol.  
     
     
         38 . The composition of  claim 37 , wherein the oligonucleotide is 8-100 nucleotides in length.  
     
     
         39 . The composition of  claim 37 , wherein the oligonucleotide is 8-40 nucleotides in length.  
     
     
         40 . The composition of  claim 37 , wherein the lipid is a cationic lipid.  
     
     
         41 . The composition of  claim 40 , wherein the oligonucleotide is ionically or covalently bound to or encapsulated within the cationic lipid.  
     
     
         42 . The composition of  claim 37 , wherein the sterol is cholesterol.  
     
     
         43 . The composition of  claim 37 , wherein the composition is administered by an oral route.  
     
     
         44 . The composition of  claim 37 , wherein the composition is administered by a parenteral route.  
     
     
         45 . The composition of  claim 37 , wherein the immune system deficiency is a viral infection.  
     
     
         46 . The composition of  claim 45 , wherein the viral infection is an HIV infection.  
     
     
         47 . The composition of  claim 37 , wherein the oligonucleotide comprises the formula  
         5′ X 1 X 2 CGX 3 X 4 3′ wherein C and G are unmethylated, X 1 , X 2 , X 3  and X 4  are nucleotides and a GCG trinucleotide sequence is not present at or near the 5′ or 3′ termini.    
     
     
         48 . The composition of  claim 37 , further comprising a pharmaceutically acceptable carrier.  
     
     
         49 . The composition of  claim 37 , wherein the oligonucleotide is synthetic.  
     
     
         50 . A method for stimulating an immune response to a vaccine in a subject comprising 
 administering to a subject a composition comprising a vaccine and an oligonucleotide delivery complex having 
 an immunostimulatory CpG containing oligonucleotide associated with a lipid or a sterol,  
   in an effective amount for stimulating an immune response.    
     
     
         51 . The method of  claim 51 , wherein the oligonucleotide is 8-100 nucleotides in length.  
     
     
         52 . The method of  claim 51 , wherein the oligonucleotide is 8-40 nucleotides in length.  
     
     
         53 . The method of  claim 51 , wherein the lipid is a cationic lipid.  
     
     
         54 . The method of  claim 54 , wherein the oligonucleotide is ionically or covalently bound to or encapsulated within the cationic lipid.  
     
     
         55 . The method of  claim 51 , wherein the sterol is cholesterol.  
     
     
         56 . The method of  claim 51 , wherein the subject has an immune system deficiency.  
     
     
         57 . The method of  claim 56 , wherein the immune system deficiency is a viral infection.  
     
     
         58 . The method of  claim 57 , wherein the viral infection is an HIV infection.  
     
     
         59 . The method of  claim 51 , wherein the oligonucleotide comprises the formula  
         5′ X 1 X 2 CGX 3 X 4  3′ wherein C and G are unmethylated, X 1 , X 2 , X 3  and X 4  are nucleotides and a GCG trinucleotide sequence is not present at or near the 5′ or 3′ termini.    
     
     
         60 . The method of  claim 51 , further comprising administering a pharmaceutically acceptable carrier to the subject.  
     
     
         61 . The method of  claim 51 , wherein the oligonucleotide is synthetic.  
     
     
         62 . The method of  claim 51 , wherein the composition is administered by an oral route.  
     
     
         63 . The method of  claim 51 , wherein the composition is administered by a parenteral route.  
     
     
         64 . The method of  claim 51 , wherein the immune response comprises increased expression of IL-12.  
     
     
         65 . The method of  claim 51 , wherein the immune response comprises increased expression of IFN-gamma.