SELECTIVE ANTISENSE COMPOUNDS AND USES THEREOF

• US 20150051389A1
• Filed: 08/08/2012
• Published: 02/19/2015
• Est. Priority Date: 08/11/2011
• Status: Abandoned Application

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Seth, Punit P., Swayze, Eric E., Oestergarrd, Michael
• Application Number:
  US14/238,439
• Publication Number:
  US 20150051389A1
• Time in Patent Office: Days
• US Class Current: 536/24.5
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/312 Phosphonates
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/316 Phosphonothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses

Abstract

Disclosed are oligomeric compounds which are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. The hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Claims

1-272. -272. (canceled)

273. 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 among 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 among 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 among;

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 target nucleic acid.

274. The oligomeric compound of claim 273, wherein the 5′

-region has a motif selected from among;

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 among;

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 among;

DDDDDD, DDDDDDD, DDDDDDDD, DDDDDDDDD, DDDDDDDDDD, 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, 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.

275. The oligomeric compound of claim 274, wherein the 5′

-region has a motif selected from among;

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.

276. The oligomeric compound of claim 274, wherein each A nucleoside comprises a bicyclic sugar moiety selected from among:

cEt, cMOE, LNA, α

-LNA, ENA and 2′

-thio LNA.

277. The oligomeric compound of claim 274, wherein each A nucleoside comprises a cEt.

278. The oligomeric compound of claim 276, wherein each B nucleoside comprises a 2′

-substituted sugar moiety comprising a 2′

-substituent selected from among;

a halogen, OCH₃, OCF₃, OCH₂CH₃, OCH₂CF₃, OCH₂—

CH═

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

O(CH₂)₂—

N(CH₃)₂, OCH₂C(═

O)—

N(H)CH₃, OCH₂C(═

O)—

N(H)—

(CH₂)₂—

N(CH₃)₂, and OCH₂—

N(H)—

C(═

NH)NH₂.

279. The oligomeric compound of claim 278, wherein each B nucleoside comprises a 2′

-substituted sugar moiety comprising a 2′

-substituent selected from among;

F, OCH₃, O(CH₂)₂—

OCH₃.

280. The oligomeric compound of claim 274, 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.

281. The oligomeric compound of claim 274, 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 FHNA.

282. The oligomeric compound of claim 274, wherein one of A or B comprises cEt, another of A or B comprises a 2′

-modified sugar moiety, and W comprises a 2-thio-thymidine nucleobase.

283. The oligomeric compound of claim 274, wherein one of A or B comprises cEt, another of A or B comprises a 2′

-modified sugar moiety, and W comprises FHNA.

284. The oligomeric compound of claim 274, wherein each A comprises MOE, each B comprises cEt, and each W is selected from among cEt or FHNA.

285. The oligomeric compound of claim 284, wherein each W comprises cEt.

286. The oligomeric compound of claim 284, wherein each W comprises 2-thio-thymidine.

287. The oligomeric compound of claim 284, wherein each W comprises FHNA.

288. The oligomeric compound of claim 274 comprising at least one modified internucleoside linkage.

289. The oligomeric compound of claim 288, wherein each internucleoside linkage is a modified internucleoside linkage.

290. The oligomeric compound of claim 289 comprising at least one phosphorothioate internucleoside linkage.

291. The oligomeric compound of claim 288 comprising at least one methylphosphonate internucleoside linkage.

292. The oligomeric compound of claim 275, wherein each A nucleoside comprises a bicyclic sugar moiety selected from among:

cEt and LNA and each B nucleoside comprises a 2′

-MOE.