Una oligomers having reduced off-target effects in gene silencing

Abstract

This invention provides UNA oligomers for gene silencing with reduced off-target effects. The UNA oligomers can have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers being UNA monomers and various nucleic acid monomers. Embodiments include pharmaceutical compositions and methods for treating or preventing TTR-related amyloidosis with reduced off-target effects by administering a UNA oligomer to a subject.

What is claimed is: 
     
         1 . A UNA oligomer for inhibiting expression of a target gene, the oligomer comprising a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the oligomer has a duplex structure of from 14 to 29 monomers in length, and wherein the oligomer has reduced off-target effects as compared to a siRNA with the same target. 
     
     
         2 . The UNA oligomer of  claim 1 , wherein the second strand is a guide strand for RNA interference, and the first strand is a passenger strand for RNA interference. 
     
     
         3 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has a UNA monomer at the first position at the 1 end of the first strand, a UNA monomer at one or both of the last two positions from the 3 end of the first strand, and a UNA monomer at one or both of the last two positions from the 3 end of the second strand. 
     
     
         4 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has a UNA monomer at the first position at the 1 end of the first strand, and a UNA monomer at one or both of the last two positions from the 3 end of the first strand. 
     
     
         5 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has a UNA monomer at the first position at the 1 end of the first strand, and a UNA monomer at one or more of the last two positions from the 3 end of the second strand. 
     
     
         6 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has a UNA monomer at the first position at the 1 end of the first strand. 
     
     
         7 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has a UNA monomer at one or more of the last two positions from the 3 end of the first strand, and a UNA monomer at one or more of the last two positions from the 3 end of the second strand. 
     
     
         8 . The UNA oligomer of  claim 1 , wherein the UNA oligomer has one or more overhangs. 
     
     
         9 . The UNA oligomer of  claim 1 , wherein the first and second strands are connected and form a duplex region with a loop at one end. 
     
     
         10 . The UNA oligomer of  claim 1 , wherein the UNA oligomer inhibits TTR expression with reduced off-target effects. 
     
     
         11 . The UNA oligomer of  claim 1 , wherein the UNA oligomer inhibits apolipoprotein gene expression with reduced off-target effects. 
     
     
         12 . The UNA oligomer of  claim 1 , wherein the oligomer inhibits TTR expression in vivo. 
     
     
         13 . The UNA oligomer of  claim 1 , wherein the UNA oligomer is targeted to inhibit gene expression in a plant with reduced off-target effects. 
     
     
         14 . The UNA oligomer of  claim 1 , comprising at least one nucleic acid monomer that is base-modified, sugar-modified, or linkage modified. 
     
     
         15 . The UNA oligomer of  claim 1 , wherein the oligomer comprises a sequence selected from the group of SEQ ID NOs:3-32. 
     
     
         16 . The UNA oligomer of  claim 1 , wherein the oligomer comprises a UNA monomer at any one or more of positions 2-8 from the 5′ end of the second strand. 
     
     
         17 . A pharmaceutical composition comprising a UNA oligomer of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the composition is capable of local or systemic administration. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the composition is capable of intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal, or oral administration. 
     
     
         20 . The pharmaceutical composition of  claim 17 , comprising a lipid formulation. 
     
     
         21 . The pharmaceutical composition of  claim 17 , comprising one or more lipids selected from cationic lipids, anionic lipids, sterols, pegylated lipids, and any combination of the foregoing. 
     
     
         22 . The pharmaceutical composition of  claim 17 , wherein the composition is substantially free of liposomes. 
     
     
         23 . The pharmaceutical composition of  claim 17 , wherein the composition contains liposomes. 
     
     
         24 . A method for treating or preventing TTR-related amyloidosis, comprising administering to a subject in need an effective amount of a UNA oligomer of  claim 1 . 
     
     
         25 . The method of  claim 24 , wherein the TTR-related amyloidosis is ATTR. 
     
     
         26 . The method of  claim 24 , wherein the subject is human. 
     
     
         27 . The method of  claim 24 , wherein the method reduces TTR in the subject with off-target effects reduced by at least 10% as compared to control. 
     
     
         28 . The method of  claim 24 , wherein the effective amount is a dose of from 0.001 to 50.0 mg/kg. 
     
     
         29 . The method of  claim 24 , wherein TTR mRNA expression is reduced for at least 5 days. 
     
     
         30 . The method of  claim 24 , wherein the method reduces peripheral neuropathy or autonomic neuropathy in the subject. 
     
     
         31 . A method for inhibiting expression of a TTR gene in a cell, comprising treating the cell with a UNA oligomer according to  claim 1 . 
     
     
         32 . A method for inhibiting expression of a TTR gene in a mammal, comprising administering to the mammal a UNA oligomer according to  claim 1 . 
     
     
         33 . A method for inhibiting expression of a gene in a plant, comprising administering to the plant a UNA oligomer having a length of from 10 to 1000 base pairs.