Use of cyclodextrins to modulate gene expression with reduced immunostimulatory response

Abstract

The present invention provides a method of reducing the immunostimulatory effects of certain phosphorothioate oligonucleotides used to treat pathogen-mediated disease states and other medical conditions. Immunostimulatory effects of phosphorothioate oligonucleotides are reduced in accordance with the method of the invention by administering the phosphorothioate oligonucleotide in a therapeutic formulation which includes at least one cyclodextrin to a mammal afflicted with the disease or condition being treated. The immune response of the mammal is also monitored in the method of the invention.

What is claimed is:  
     
         1 . A method of reducing an immunostimulatory response of a mammal to a phosphorothioate oligonucleotide which comprises the steps of: 
 a) administering a therapeutic formulation containing the phosphorothioate oligonucleotide and at least one cyclodextrin to the mammal; and    b) monitoring the immune response of the mammal.    
     
     
         2 . The method of  claim 1  wherein the cyclodextrin is selected from the group consisting of a β-cyclodextrin, a γ-cyclodextrin, a substituted cyclodextrin, and a derivative of a cyclodextrin.  
     
     
         3 . The method of  claim 2  wherein the β-cyclodextrin is selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin and 2-hydroxyethyl-β-cyclodextrin.  
     
     
         4 . The method of  claim 2  wherein the γ-cyclodextrin is hydroxypropyl-γ-cyclodextrin.  
     
     
         5 . The method of  claim 2  wherein the derivative of the cyclodextrin is selected from the group consisting of a β-cyclodextrin polysulfate and a γ-cyclodextrin polysulfate.  
     
     
         6 . The method of  claim 1  wherein the therapeutic formulation contains a mixture of cyclodextrins.  
     
     
         7 . The method of  claim 1  wherein the phosphorothioate oligonucleotide is modified.  
     
     
         8 . A method of reducing an immunostimulatory response of a mammal to a protein which comprises the steps of: 
 a) administering a therapeutic formulation containing the protein and at least one cyclodextrin to the mammal; and    b) monitoring the immune response of the mammal.    
     
     
         9 . The method of  claim 8  wherein the therapeutic formulation comprises a protein-cyclodextrin complex.