Selective Antisense Compounds and Uses Thereof

Abstract

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

1 . A oligomeric compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides, wherein the modified oligonucleotide has a modification motif comprising:
 a 5′-region consisting of 2-8 linked 5′-region nucleosides, each independently selected from a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 5′-region nucleoside is a modified nucleoside and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;   a 3′-region consisting of 2-8 linked 3′-region nucleosides, each independently selected from a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 3′-region nucleoside is a modified nucleoside and wherein the 5′-most 3′-region nucleoside is a modified nucleoside; and   a central region between the 5′-region and the 3′-region consisting of 6-12 linked central region nucleosides, each independently selected from: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside;   wherein the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target region of a nucleic acid associated with a huntingtin transcript.   
     
     
         2 . (canceled) 
     
     
         3 . The oligomeric compound of  claim 1 , the nucleobase sequence of the target region of the target nucleic acid differs from the nucleobase sequence of at least one non-target nucleic acid by a single differentiating nucleobase. 
     
     
         4 .- 7 . (canceled) 
     
     
         8 . The oligomeric compound of  claim 3 , wherein the single differentiating nucleobase is a single-nucleotide polymorphism, and wherein the single-nucleotide polymorphism is selected from: rs6446723, rs3856973, rs2285086, rs363092, rs916171, rs6844859, rs7691627, rs4690073, rs2024115, rs11731237, rs362296, rs10015979, rs7659144, rs363096, rs362273, rs16843804, rs362271, rs362275, rs3121419, rs362272, rs3775061, rs34315806, rs363099, rs2298967, rs363088, rs363064, rs363102, rs2798235, rs363080, rs363072, rs363125, rs362303, rs362310, rs10488840, rs362325, rs35892913, rs363102, rs363096, rs11731237, rs10015979, rs363080, rs2798235, rs1936032, rs2276881, rs363070, rs35892913, rs12502045, rs6446723, rs7685686, rs3733217, rs6844859, and rs362331. 
     
     
         9 .- 20 . (canceled) 
     
     
         21 . The oligomeric compound of  claim 1 , wherein at least one central region nucleoside is a modified nucleoside. 
     
     
         22 .- 31 . (canceled) 
     
     
         32 . The oligomeric compound of  claim 21 , wherein at least one modified central region nucleoside comprises a 2′-substituted sugar moiety comprising a 2′ substituent selected from: halogen, optionally substituted allyl, optionally substituted amino, azido, optionally substituted SH, CN, OCN, CF 3 , OCF 3 , O, S, or N(R m )-alkyl; O, S, or N(R m )-alkenyl; O, S or N(R m )-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aralkyl, optionally substituted O-alkaryl, optionally substituted O-aralkyl, O(CH 2 ) 2 SCH 3 , O—(CH 2 ) 2 —O—N(R m )(R n ) or O—CH 2 —C(═O)—N(R m )(R n ), where each R m  and R n  is, independently, H, an amino protecting group or substituted or unsubstituted C 1 -C 10  alkyl;
 wherein each optionally substituted group is optionally substituted with a substituent group independently selected from: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy (S alkyl), halogen, alkyl, aryl, alkenyl and alkynyl. 
 
     
     
         33 .- 43 . (canceled) 
     
     
         44 . The oligomeric compound of  claim 21 , wherein the 2 nd , 3 rd , 4 th , 5 th , 6 th , 7 th , or 8 th  nucleoside from the 5′-end of the central region is a modified nucleoside. 
     
     
         45 .- 61 . (canceled) 
     
     
         62 . The oligomeric compound of  claim 1 , wherein the central region has a nucleoside motif selected from: DDDDDDDDDD, DDDDXDDDDD; DDDDDXDDDDD; DDDXDDDDD; DDDDXDDDDDD; DDDDXDDDD; DDXDDDDDD; DDDXDDDDDD; DXDDDDDD; DDXDDDDDDD; DDXDDDDD; DDXDDDXDDD; DDDXDDDXDDD; DXDDDXDDD; DDXDDDXDD; DDXDDDDXDDD; DDXDDDDXDD; DXDDDDXDDD; DDDDXDDD; DDDXDDD; DXDDDDDDD; DDDDXXDDD; DXXDXXDXX; DDDDDDDDD; DXDDDDDDD; DDXDDDDDD; DDDXDDDDD; DDDDXDDDD; DDDDDXDDD; DDDDDDXDD; DDDDDDDXD; DXXDDDDDD; DDDDDDXXD; DDXXDDDDD; DDDXXDDDD; DDDDXXDDD; DDDDDXXDD; DXDDDDDXD; DXDDDDXDD; DXDDDXDDD; DXDDXDDDD; DXDXDDDDD; DDXDDDDXD; DDXDDDXDD; DDXDDXDDD; DDXDXDDDD; DDDXDDDXD; DDDXDDXDD; DDDXDXDDD; DDDDXDDXD; DDDDXDXDD; DDDDDXDXD; DDDDDD, DDDDDDD, DDDDDDDD, DDDDDDDDD, DDDDDDDDDD, DXDDDD, DDXDDD, DDDXDD, DDDDXD, DXDDDDD, DDXDDDD, DDDXDDD, DDDDXDD, DDDDDXD, DXDDDDDD, DDXDDDDD, DDDXDDDD, DDDDXDDD, DDDDDXDD, DDDDDDXD, DXDDDDDDD; DDXDDDDDD, DDDXDDDDD, DDDDXDDDD, DDDDDXDDD, DDDDDDXDD, DDDDDDDXD, DXDDDDDDDD, DDXDDDDDDD, DDDXDDDDDD, DDDDXDDDDD, DDDDDXDDDD, DDDDDDXDDD, DDDDDDDXDD, and DDDDDDDDXD; wherein
 each D is an unmodified deoxynucleoside; and each X is a modified nucleoside.   
     
     
         63 .- 72 . (canceled) 
     
     
         73 . The oligomeric compound of  claim 62 , wherein the nucleobase sequence of the target region of the target nucleic acid differs from the nucleobase sequence of at least one non-target nucleic acid by a single differentiating nucleobase, and wherein the location of the single differentiating nucleobase is represented by X. 
     
     
         74 .- 101 . (canceled) 
     
     
         102 . The oligomeric compound of  claim 1 , wherein the 5′-region has a motif selected from:
 ADDA; ABDAA; ABBA; ABB; ABAA; AABAA; AAABAA; AAAABAA; AAAAABAA; AAABAA; AABAA; ABAB; ABADB; ABADDB; AAABB; AAAAA; ABBDC; ABDDC; ABBDCC; ABBDDC; ABBDCC; ABBC; AA; AAA; AAAA; AAAAB; AAAAAAA; AAAAAAAA; ABBB; AB; ABAB; AAAAB; AABBB; AAAAB; AABBB, AAA, BBB, BBBAA, AAB, BAA, BBAA, AABB, AAAB, ABBW, ABBWW, ABBB, ABBBB, ABAB, ABABAB, ABABBB, ABABAA, AAABB, AAAABB, AABB, ABBBB, BBBBB, AAABW, BBBBAA, and AAABW; 
 wherein each A is a modified nucleoside of a first type, each B is a modified nucleoside of a second type, each C and each W is a modified nucleoside of a third type, and each D is an unmodified deoxynucleoside. 
 
     
     
         103 .- 175 . (canceled) 
     
     
         176 . The oligomeric compound of  claim 1 , wherein the 3′-region has a motif selected from: ABB, ABAA, AAABAA, AAAAABAA, AABAA, AAAABAA, AAABAA, ABAB, AAAAA, AAABB, AAAAAAAA, AAAAAAA, AAAAAA, AAAAB, AAAA, AAA, AA, AB, ABBB, ABAB, AABBB, BBA, AAB, AAA, BBB, BBAA, AABB, WBBA, WAAB, BBBA, BBBBA, BBBB, BBBBBA, ABBBBB, BBAAA, AABBB, BBBAA, BBBBA, BBBBB, BABA, BBAAAA, AABBBB, BAAAA, and ABBBB, wherein each A is a modified nucleoside of a first type, each B is a modified nucleoside of a second type, and each W is a modified nucleoside of a first type, a second type, or a third type. 
     
     
         177 .- 203 . (canceled) 
     
     
         204 . The oligomeric compound of  claim 1 , wherein the 5′-region has a motif selected from: AB, ABB, AAA, BBB, BBBAA, AAB, BAA, BBAA, AABB, AAAB, ABBW, ABBWW, ABBB, ABBBB, ABAB, ABABAB, ABABBB, ABABAA, AAABB, AAAABB, AABB, AAAAB, AABBB, ABBBB, BBBBB, AAABW, AAAAA, and BBBBAA;
 wherein the 3′-region has a motif selected from: BBA, AAB, AAA, BBB, BBAA, AABB, WBBA, WAAB, BBBA, BBBBA, BBBB, BBBBBA, ABBBBB, BBAAA, AABBB, BBBAA, BBBBA, BBBBB, BABA, AAAAA, BBAAAA, AABBBB, BAAAA, and ABBBB; 
 wherein the central region has a nucleoside motif selected from: DDDDDD, DDDDDDD, DDDDDDDD, DDDDDDDDD, DDDDDDDDDD, DXDDDDDDD, DDXDDDDDD, DDDXDDDDD, DDDDXDDDD, DDDDDXDDD, DDDDDDXDD, DDDDDDDXD, DXXDDDDDD, DDDDDDXXD, DDXXDDDDD, DDDXXDDDD, DDDDXXDDD, DDDDDXXDD, DXDDDDDXD, DXDDDDXDD, DXDDDXDDD, DXDDXDDDD, DXDXDDDDD, DDXDDDDXD, DDXDDDXDD, DDXDDXDDD, DDXDXDDDD, DDDXDDDXD, DDDXDDXDD, DDDXDXDDD, DDDDXDDXD, DDDDXDXDD, and DDDDDXDXD, DDDDDDDD, DXDDDDDD, DDXDDDDD, DDDXDDDD, DDDDXDDD, DDDDDXDD, DDDDDDXD, DXDDDDXD, DXDDDXDD, DXDDXDDD, DXDXDDDD, DXXDDDDD, DDXXDDDD, DDXDXDDD, DDXDDXDD, DXDDDDXD, DDDXXDDD, DDDXDXDD, DDDXDDXD, DDDDXXDD, DDDDXDXD, and DDDDDXXD, DXDDDDD, DDXDDDD, DDDXDDD, DDDDXDD, DDDDDXD, DXDDDXD, DXDDXDD, DXDXDDD, DXXDDDD, DDXXDDD, DDXDXDD, DDXDDXD, DDDXXDD, DDDXDXD, and DDDDXXD, DXDDDD, DDXDDD, DDDXDD, DDDDXD, DXXDDD, DXDXDD, DXDDXD, DDXXDD, DDXDXD, and DDDXXD; and 
 wherein each A is a modified nucleoside of a first type, each B is a modified nucleoside of a second type, each W is a modified nucleoside of a first type, a second type, or a third type, each D is an unmodified deoxynucleoside, and each X is a modified nucleoside or a modified nucleobase. 
 
     
     
         205 . The oligomeric compound of  claim 204 , wherein the 5′-region has a motif selected from:
 AB, ABB, AAA, BBB, BBBAA, AAB, BAA, BBAA, AABB, ABBW, ABBWW, ABBB, ABBBB, ABAB, ABABAB, ABABBB, ABABAA, AAABB, AAAABB, AABB, AAAAB, AABBB, ABBBB, BBBBB, AAABW, and BBBBAA; and wherein the 3′-region has a BBA motif. 
 
     
     
         206 . The oligomeric compound of  claim 204 , wherein one of A or B comprises a bicyclic sugar moiety, another of A or B comprises a 2′-MOE sugar moiety, and W comprises a 2-thio-thymidine nucleobase or FHNA. 
     
     
         207 .- 213 . (canceled) 
     
     
         214 . The oligomeric compound of  claim 1  comprising at least one modified internucleoside linkage. 
     
     
         215 .- 217 . (canceled) 
     
     
         218 . The oligomeric compound of  claim 214  comprising one or two methylphosphonate internucleoside linkages. 
     
     
         219 . (canceled) 
     
     
         220 . The oligomeric compound of  claim 218 , wherein at least one of the 3 rd , 4 th , 5 th , 6 th  and/or 7 th  internucleoside from the 5′-end and/or from the 3′-end is a methylphosphonate internucleoside linkage. 
     
     
         221 . (canceled) 
     
     
         222 . The oligomeric compound of  claim 218 , wherein at least one of the 3 rd , 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , 10 th , 11 th , and/or 12 th  internucleoside from the 5′-end is a methylphosphonate internucleoside linkage, and wherein at least one of the 3 rd , 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , 10 th , 11 th , and/or 12 th  nucleoside from the 5′-end is a modified nucleoside. 
     
     
         223 . The oligomeric compound of  claim 218 , wherein at least one of the 3 rd , 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , 10 th , 11 th , and/or 12 th  internucleoside from the 3′-end is a methylphosphonate internucleoside linkage, and wherein at least one of the 3 rd , 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , 10 th , 11th, and/or 12th nucleoside from the 3′-end is a modified nucleoside. 
     
     
         224 . The oligomeric compound of  claim 1  comprising at least one conjugate group. 
     
     
         225 .- 259 . (canceled) 
     
     
         260 . A method comprising contacting a cell with an oligomeric compound of  claim 1 . 
     
     
         261 .- 265 . (canceled) 
     
     
         266 . A method comprising administering a pharmaceutical composition comprising the oligomeric compound of  claim 1  to an animal. 
     
     
         267 .- 269 . (canceled) 
     
     
         270 . A method of ameliorating a symptom of Huntington's disease, comprising administering an oligomeric compound of  claim 1  to an animal in need thereof. 
     
     
         271 .- 272 . (canceled)