Double-stranded oligonucleotides

Abstract

Antisense sequences, including duplex RNAi compositions, which possess improved properties over those taught in the prior art are disclosed. The invention provides optimized antisense oligomer compositions and method for making and using the both in in vitro systems and therapeutically. The invention also provides methods of making and using the improved antisense oligomer compositions.

1 .- 13 . (canceled) 
     
     
         14 . A composition comprising a double-stranded oligonucleotide molecule, the molecule comprising:
 a first strand and a second strand each having a length of less than 25 nucleotides;   wherein at least one but not all of the nucleotides of at least one strand comprises a 2′-O-methyl modification, and   wherein said double-stranded oligonucleotide molecule is chemically synthesized.   
     
     
         15 . The composition of  claim 14 , wherein a strand of said double-stranded oligonucleotide molecule is complementary to a portion of a target nucleic acid. 
     
     
         16 . The composition of  claim 15  wherein the double-stranded oligonucleotide molecule has a duplex length of at least 10 nucleotides. 
     
     
         17 . The composition of  claim 15  wherein the target nucleic acid is a mRNA and the at least one strand comprising a 2′-O-methyl modification is an antisense strand. 
     
     
         18 . The composition of  claim 17  wherein the target nucleic acid is present within a cell. 
     
     
         19 . The composition of  claim 14  wherein the double-stranded oligonucleotide molecule is a double-stranded ribonucleic acid molecule. 
     
     
         20 . The composition of  claim 14  wherein the duplex length is at least 15 nucleotides. 
     
     
         21 . A composition comprising a double-stranded oligonucleotide molecule, the molecule comprising:
 a first strand and a second strand each having a length of less than 25 nucleotides;   wherein at least one but not all of the nucleotides of at least one strand comprises a 2-modification,   wherein at least one strand comprises an end blocking group, and   wherein said double-stranded oligonucleotide molecule is chemically synthesized.   
     
     
         22 . The composition of  claim 21  wherein the double-stranded oligonucleotide molecule has a duplex length of at least 10 nucleotides. 
     
     
         23 . The composition of  claim 21  wherein the 2′-modification is a 2′-O-methyl modification. 
     
     
         24 . The composition of  claim 21  wherein the end blocking group is an exonuclease resistant structure. 
     
     
         25 . A composition comprising a double-stranded oligonucleotide molecule, the molecule comprising:
 a first strand and a second strand each having a length of less than 25 nucleotides;   wherein at least one but not all of the nucleotides of at least one strand comprises a 2′-O-methyl modification,   wherein the oligonucleotide molecule is coupled to a ligand for a cellular receptor, and   wherein said double-stranded oligonucleotide molecule is chemically synthesized.   
     
     
         26 . The composition of  claim 25  wherein the double-stranded oligonucleotide molecule has a duplex length of at least 10 nucleotides. 
     
     
         27 . The composition of  claim 25  wherein the double-stranded oligonucleotide molecule is coupled to a ligand for a cellular receptor. 
     
     
         28 . The composition of  claim 14  wherein the double-stranded oligonucleotide molecule is linked to a carrier group which is attached to a targeting moiety. 
     
     
         29 . A method for introducing a double-stranded oligonucleotide molecule comprising a first strand and a second strand into a eukaryotic cell in vitro, the method comprising contacting the eukaryotic cell with the double-stranded oligonucleotide molecule of  claim 14  to result in the double-stranded oligonucleotide molecule being introduced into the eukaryotic cell. 
     
     
         30 . A method of treating a patient having a disease involving the expression of a protein, comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 , wherein a strand of the double-stranded oligonucleotide molecule is complementary to a sequence of target nucleic acid involved in expression of the protein, wherein the disease is cancer, retinopathy, an autoimmune disease, an inflammatory disease, a viral disease or a cardiovascular disease. 
     
     
         31 . A method of treating a patient having a disease involving the expression of a protein, comprising administering to the patient a therapeutically effective amount of the composition of  claim 21 , wherein a strand of the double-stranded oligonucleotide molecule is complementary to a sequence of target nucleic acid involved in expression of the protein, wherein the disease is cancer, retinopathy, an autoimmune disease, an inflammatory disease, a viral disease or a cardiovascular disease. 
     
     
         32 . A method of treating a patient having a disease involving the expression of a protein, comprising administering to the patient a therapeutically effective amount of the composition of  claim 25 , wherein a strand of the double-stranded oligonucleotide molecule is complementary to a sequence of target nucleic acid involved in expression of the protein, wherein the disease is cancer, retinopathy, an autoimmune disease, an inflammatory disease, a viral disease or a cardiovascular disease.