Modified protein kinase A-specifc oligonucleotides and methods of their use

Abstract

Disclosed are synthetic, modified oligonucleotides complementary to, and capable of down-regulating the expression of, nucleic acid encoding protein kinase A subunit RI α . The modified oligonucleotides have from about 15 to about 30 nucleotides and are hybrid, inverted hybrid, or inverted chimeric oligonucleotides. Also disclosed are therapeutic compositions containing such oligonucleotides and methods of using the same.

What is claimed is:  
     
         1 . A method of inhibiting the proliferation of cancer cells, comprising the step of administering to the cells a synthetic, modified oligonucleotide complementary to, and capable of down-regulating the expression of, nucleic acid encoding protein kinase A subunit RI α , the modified oligonucleotide having from about 15 to about 30 nucleotides and being a hybrid, inverted hybrid, or inverted chimeric oligonucleotide, 
 the hybrid oligonucleotide comprising a region of at least two deoxyribonucleotides, flanked by 3′ and 5′ flanking ribonucleotide regions each having at least four ribonucleotides,    the inverted hybrid oligonucleotide comprising a region of at least four ribonucleotides flanked by 3′ and 5′ flanking deoxyribonucleotide regions of at least two deoxyribonucleotides, and    the inverted chimeric oligonucleotide comprising an oligonucleotide nonionic region of at least four nucleotides flanked by two oligonucleotide phosphorothioate regions.    
     
     
         2 . The method of  claim 1 , wherein the oligonucleotide is a hybrid oligonucleotide.  
     
     
         3 . The method of  claim 2 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not hybrid.  
     
     
         4 . The method of  claim 1 , wherein the oligonucleotide is an inverted hybrid oligonucleotide.  
     
     
         5 . The method of  claim 4 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not inverted hybrid.  
     
     
         6 . The method of  claim 1 , wherein the oligonucleotide is an inverted chimeric oligonucleotide.  
     
     
         7 . The method of  claim 6 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not inverted chimeric.  
     
     
         8 . A method of treating cancer in an afflicted subject, comprising the step of administering to the subject a therapeutic composition comprising a synthetic, modified oligonucleotide complementary to, and capable of down-regulating the expression of, nucleic acid encoding protein kinase A subunit RI α , the modified oligonucleotide having from about 15 to about 30 nucleotides and being a hybrid, inverted hybrid, or inverted chimeric oligonucleotide, 
 the hybrid oligonucleotide comprising a region of at least two deoxyribonucleotides, flanked by 3′ and 5′ flanking ribonucleotide regions each having at least four ribonucleotides,    the inverted hybrid oligonucleotide comprising a region of at least four ribonucleotides flanked by 3′ and 5′ flanking deoxyribonucleotide regions of at least two deoxyribonucleotides, and the inverted chimeric oligonucleotide comprising an oligonucleotide nonionic region of at least four nucleotides flanked by two oligonucleotide phosphorothioate regions.    
     
     
         9 . The method of  claim 8 , wherein the oligonucleotide is a hybrid oligonucleotide.  
     
     
         10 . The method of  claim 9 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not hybrid.  
     
     
         11 . The method of  claim 8 , wherein the oligonucleotide is an inverted hybrid oligonucleotide.  
     
     
         12 . The method of  claim 11 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not inverted hybrid.  
     
     
         13 . The method of  claim 8 , wherein the oligonucleotide is an inverted chimeric oligonucleotide.  
     
     
         14 . The method of  claim 13 , wherein there is reduced mitogenicity, reduced activation of complement, or reduced antithrombotic properties, relative to the side effects caused by an oligonucleotide which is not inverted chimeric.