CONJUGATED OLIGONUCLEOTIDES
Provided herein are conjugated oligonucleotides that are characterized by efficient and specific tissue distribution.
1 - 148 . (canceled)
149 . A compound comprising a structure of:
an ionized form thereof, or a salt thereof.
150 . The compound of claim 149 , wherein the oligonucleotide is a double-stranded nucleic acid comprising a first oligonucleotide and a second oligonucleotide, wherein:
(1) the first oligonucleotide comprises at least 16 contiguous nucleotides, a 5′ end, a 3′ end, and has complementarity to a target;
(2) the second oligonucleotide comprises at least 15 contiguous nucleotides, a 5′ end, a 3′ end, and has homology with a target; and
(3) a portion of the first oligonucleotide is complementary to a portion of the second oligonucleotide.
151 . The compound of claim 150 , wherein the first oligonucleotide comprises a chemical modification at a 2′-OH sugar position of each nucleotide.
152 . The compound of claim 151 , wherein the chemical modification at the sugar position of the nucleotides comprises a 2′-methoxy chemical modification or a 2′-fluoro modification.
153 . The compound of claim 152 , wherein the nucleotides at positions 2 and 14 from the end of the first oligonucleotide are not 2′-methoxy-ribonucleotides.
154 . The compound of claim 150 , wherein the second oligonucleotide comprises a chemical modification at a 2′-OH sugar position of each nucleotide.
155 . The compound of claim 154 , wherein the chemical modification at the sugar position of the nucleotides comprises a 2′-methoxy chemical modification or a 2′-fluoro modification.
156 . The compound of claim 155 , wherein the nucleotides at position 2 from the 5′ end of the second oligonucleotide is a 2′-methoxy-ribonucleotide.
157 . The compound of claim 150 , wherein the nucleotides of the first oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages.
158 . The compound of claim 157 , wherein the nucleotides at positions 1-7 from the 3′ end of the first oligonucleotide are connected to adjacent nucleotides via phosphorothioate linkages.
159 . The compound of claim 157 , wherein the nucleotides at positions 1 and 2 from the end of the first nucleotide are connected to adjacent nucleotides via phosphorothioate linkages.
160 . The compound of claim 150 , wherein the nucleotides of the second oligonucleotide are connected to adjacent nucleotides via phosphodiester or phosphorothioate linkages.
161 . The compound of claim 160 , wherein the second oligonucleotide comprises a dT-dT moiety at the 3′ end.
162 . The compound of claim 161 , wherein the nucleotides at positions 1 and 2 from the 3′ end of the second nucleotide are connected to adjacent nucleotides via phosphorothioate linkages.
163 . The compound of claim 162 , wherein the nucleotides at positions 1 and 2 from the 5′ end of the second nucleotide are connected to adjacent nucleotides via phosphorothioate linkages.
164 . The compound of claim 150 , wherein the first oligonucleotide comprises a moiety X at the 5′ end, wherein X is selected from the group consisting of:
165 . The compound of claim 164 , wherein X is X3.
166 . The compound of claim 150 , wherein the target is soluble FLT.
167 . A pharmaceutical composition comprising the compound of claim 149 .
168 . A method for treating a disease or disorder in a subject, comprising administering to the subject the compound of claim 149 .
169 . The method of claim 168 , wherein the disease or disorder is an angiogenic disease or disorder.
170 . The method of claim 169 , wherein the angiogenic disease or disorder is pre-eclampsia (PE), postpartum PE, eclampsia, or HELLP.