Linkage modified oligomeric compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2025154506-A1
Application number	US-202218264705-A
Country	US
Kind code	A1
Filing date	Feb 11, 2022
Priority date	Feb 11, 2021
Publication date	May 15, 2025
Grant date	—

Abstract

The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one chemical modification.

First claim

1 .- 25 . (canceled)

26 . An RNAi agent, comprising an antisense RNAi oligomeric compound comprising an antisense RNAi oligonucleotide consisting of 21-25 linked nucleosides and a sense RNAi oligomeric compound comprising a sense RNAi oligonucleotide consisting of 19-23 linked nucleosides, wherein the antisense RNAi oligonucleotide comprises a 5′-stabilized phosphate group; and at least one internucleoside linkage of Formula I:

wherein independently for each internucleoside linkage of Formula I:
X is selected from O or S, and
R is selected from aryl, a substituted aryl, a heterocycle, a substituted heterocycle, an aromatic heterocycle, a substituted aromatic heterocycle, a diazole, a substituted diazole, a C 1 -C 6 alkoxy, C 1 -C 20 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 20 alkyl, substituted C 2 -C 6 alkenyl substituted C 2 -C 6 alkynyl, and a conjugate group; and
wherein each of at least three sugar moieties of the nucleosides of the antisense RNAi oligonucleotide is selected from a 2′-O-methyl-β-D-ribosyl sugar moiety, a 2′-O-methoxyethyl β-D-ribosyl sugar moiety, a sugar surrogate, a stereo-non-standard sugar moiety, a 2′-β-D-deoxyribosyl sugar moiety, a β-D-ribosyl sugar moiety, and 2′-fluoro-β-D-ribosyl sugar moiety, and wherein each of at least three such sugar moieties are different from one another.

27 . The RNAi agent of claim 26 , wherein for at least one internucleoside linkage of Formula I, X is O and R is methyl.

28 . The RNAi agent of any of claim 26 , wherein for each internucleoside linkage of Formula I, X is O and R is methyl.

29 . The RNAi agent of claim 26 , wherein each internucleoside linkage of the antisense RNAi oligonucleotide is selected from an internucleoside linkage of Formula I, a phosphodiester internucleoside linkage, and a phosphorothioate internucleoside linkage.

30 . The RNAi agent of claim 26 , wherein the antisense RNAi oligonucleotide has an internucleoside linkage motif selected from sz(o) n zs, ss(o) n zs, and sz(o) n ss, wherein each “s” is a phosphorothioate internucleoside linkage, each “z” is an internucleoside linkage of Formula I, each “o” is a phosphodiester internucleoside linkage, and n is from 16-20.

31 . The RNAi agent of claim 26 , wherein the antisense RNAi oligonucleotide consists of 23 linked nucleosides.

32 . The RNAi agent of claim 31 , wherein the antisense RNAi oligonucleotide has an internucleoside linkage motif selected from zsooooooooooooooooooss, szooooooooooooooooooss, zzooooooooooooooooooss, zzoooooooooooooooooozs, ssoooozoooooooooooooss, ssoooooooooooooooooozz, zsoooooooooooooooooozz, zsooozoooooooooooooozz, ssoooooooooooooooooosz, ssoooooooooooooooooozs, szoooooooooooooooooosz, zsoooooooooooooooooosz, zsoooooooooooooooooozs, szoooooooooooooooooozs, szooozooooooozozooooss, ssooozooooooozozooooss, ssooooooooooozozooooss, szooooooooooozooooooss, zoooooooooooooooooooss, szoooooooooooooooooozz, ssooosooooooososooooss, ssooozooooooooooooooss, ssooooooooooooozooooss, ssooooooooooozooooooss wherein each “s” is a phosphorohioate internucleoside linkage, each “z” is an internucleoside linkage of Formula I or of Formula XIV, and each “o” is a phosphodiester internucleoside linkage.

33 . The RNAi agent of claim 32 , wherein for each internucleoside linkage of Formula I, X is O and R is methyl.

34 . The RNAi agent of claim 26 , wherein each stereo-non-standard sugar moiety is independently selected from a 2′-fluoro-β-D-xylosyl sugar moiety, a 2′-fluoro-β-D-arabinosyl sugar moiety, 2′-O-methyl-β-D-xylosyl sugar moiety, and a 2′-β-D-deoxyxylosyl sugar moiety.

35 . The RNAi agent of claim 26 , wherein each sugar surrogate is independently selected from fluoro hexitol nucleic acid (F-HNA), hexitol nucleic acid (HNA) or altritol nucleic acid (ANA).

36 . The RNAi agent of claim 26 , wherein the antisense RNAi oligonucleotide comprises no more than three 2′-fluoro-β-D-ribosyl sugar moieties.

37 .- 45 . (canceled)

46 . The RNAi agent of claim 31 , wherein the antisense RNAi oligonucleotide has a sugar motif selected from: y[f2bDx]yyyfyyyyyyyfyfyyyyyyy, yfyyy[f2bDx]yyyyyyyfyfyyyyyyy, yfyyyfyyyyyyy[f2bDx]yfyyyyyyy, yfyyyfyyyyyyyfy[f2bDx]yyyyyyy, y[f2bDx]yyy[f2bDx]yyyyyyy[f2bDx]y[f2bDx]yyyyyyy, efyyyfy[16C 2 r]yyyyyfyfyyyyyyy, e[f2bDx]yyyfyyyyyyyfyfyyyyyyy, efyyy[f2bDx]yyyyyyyfyfyyyyyyy, efyyyfyyyyyyy[f2bDx]yfyyyyyyy, efyyyfyyyyyyyfy[f2bDx]yyyyyyy, e[f2bD) x]yyy[f2bDx]yyyyyyy[f2bDx]y[f2bDx]yyyyyyy, efyyy[F-HNA]yyyyyyyfyfyyyyyyy, efyyyfyyyyyyy[F-HNA]yfyyyyyyy, efyyyfyyyyyyyfy[F-HNA]yyyyyyy, yfyyydyyyyyyyfyfyyyyyyy, yfyyyfyyyyyyydyfyyyyyyy, yfyyyfyyyyyyyfydyyyyyyy, yfyyydyyyyyyydydyyyyyyy, yryyyfyyyyyyyfyfyyyyyyy, yfyyyyyyyyyyfyfyyyyyyy, yfyyyfyyyyyyyryfyyyyyyy, yfyyyfyyyyyyyfyryyyyyyy, yryyyryyyyyyyryryyyyyyy, y[bDdx]yyyfyyyyyyyfyfyyyyyyy, yfyyy[bDdx]yyyyyyyfyfyyyyyyy, yfyyyfyyyyyyy[bDdx]yfyyyyyyy, yfyyyfyyyyyyyfy[bDdx]yyyyyyy, y[bDdx]yyy[bDdx]yyyyyyy[bDdx]y[bDdx]yyyyyyy, y[F-HNA]yyyfyyyyyyyfyfyyyyyyy, yfyyy[F-HNA]yyyyyyyfyfyyyyyyy, yfyyyfyyyyyyy[F-HNA]yfyyyyyyy, yfyyyfyyyyyyyfy[F-HNA]yyyyyyy, y[F-HNA]yyy[F-HNA]yyyyyyy[F-HNA]y[F-HNA]yyyyyyy, yfyyyfyyyyyyy[2bDx]yfyyyyyyy, y[bDa]yyyfyyyyyyyfyfyyyyyyy, yfyyy[bDa]yyyyyyyfyfyyyyyyy, yfyyyfyyyyyyy[bDa]yfyyyyyyy, yfyyyfyyyyyyyfy[bDa]yyyyyyy, y[bDa]yyy[bDa]yyyyyyy[bDa]y[bDa]yyyyyyy, yfyyyfyyyyyyy[bDx]yfyyyyyyy, yfyyyfyffyyyyfyfyyyyydd, yfyyyfyffyyyyfyfyyyyy[bLdr][bLdr], yfyyyfyffyyyyfyfyyyyy[aDdr][aDdr], yfyyyfyffyyyyfyfyyyyy[bDdx][bDdx], yfyyyfyffyyyyfyfyyyyy[bLdx][bLdx], yfyyyfyffyyyyfyfyyyyy[aDdx][aDdx], yfyyyfyffyyyyfyfyyyyy[aLdx][aLdx], yfyyyfyyyyyyyfyfyyyyyee, yfyyyfyyyyyyyfyfyyyyykk, yfyyyfyyyyyyyfyfyyyyy[LNA][LNA], yfyyyfyyyyyyyfyfyyyyy[F-HNA][F-HNA], [ANA]fyyyfyyyyyyyfyfyyyyyyy, y[ANA]yyyfyyyyyyyfyfyyyyyyy, yfyyyf[ANA]yyyyyyfyfyyyyyyy, yfyyyfyy[ANA]yyyyfyfyyyyyyy, yfyyyfyyyyyyy[ANA]yfyyyyyyy, yfyyyfyyyyyyyfyf[ANA]yyyyyy, yfyyyfyy[ANA]yyyy[ANA]yf[ANA]yyyyy[ANA], yfyyyfyyyyyyyfyfyyyyyyk, yfyyyfyyyyyyyfyfyyyyyke, yfyyyfyyyyyyyfyfyyyyyky, efyyydyyyyyyydydyyyyyyy, yfyyyfyyyyyyy[ANA]yf[ANA]yyyyyy, yfyyyfyyyyyyyfyfyyyyy[ANA]y, yfyyyfyyyyyyyfyfyyyyy[f2bDa][f2bDa], yfyyyfyyyyyyyfyfyyyyynn, yfyyyfyyyyyyyfyfyyyyy[DMAEOE][DMAEOE], yfyyyfyyyyyyyfyfyyyyy[HNA][HNA], yfyyyfyyyyyyyfyfyyyyy[SM5LNA][SM5LNA], yfyyyfyyyyyyyfyfyyyyy[DMAOE][DMAOE], yfyyyfyyyyyyyfyfyyyyydd, yfyyyfyyyyyyyfyfyyyyy[aLdr][aLdr], [HNA]fyyyfyyyyyyyfyfyyyyyyy, dfyyyfyyyyyyyfyfyyyyyyy, y[HNA]yyyfyyyyyyyfyfyyyyyyy, e[HNA]yyyfyyyyyyyfyfyyyyyyy, yfyyyf[HNA]yyyyyyfyfyyyyyyy, yfyyyfyy[HNA]yyyyfyfyyyyyyy, yfyyyfyyyyyyy[HNA]yfyyyyyyy, yfyyyfyyyyyyyfyf[HNA]yyyyyy, yfyyyfyy[HNA]yyyy[HNA]yf[HNA]yyyyy[HNA], yfyyyfyyyyyyy[HNA]yf[HNA]yyyyyy, yfyyyfyyyyyyyfyfyyyyy[HNA]y, kfyyyfyyyyyyyfyfyyyyyyy, e[F-HNA]yyyfyyyyyyyfyfyyyyyyy, e[LNA]yyyfyyyyyyyfyfyyyyyyy, edyyyfyyyyyyyfyfyyyyyyy, edyyydyyyyyyydydyyyyyyy, ydyyyfyyyyyyyfyfyyyyyyy, ydyyydyyyyyyydydyyyyyyy, efyyfyfyyyyfyfyyyyyyyyy, edyydydyyyydyfyyyyyyyyy, efyyyfyyyyyyyfyfyyyyydd, [F-HNA]fyyyfyyyyyyyfyfyyyyyyy, eyyyyfyyyyyyyfyfyyyyyyy, eryyyryyyyyyyryryyyyyyy, efyyydyyyyyyyfyfyyyyyyy, efyyyfyyyyyyyfydyyyyyyy, efyyyfyyyyyyydyfyyyyyyy; wherein “f” represents a 2′-fluoro-β-D-ribosyl sugar moiety, “y” represents a 2′-O-methyl-β-D-ribosyl sugar moiety, “e” represents a 2′-O-methyoxyethyl-β-D-ribosyl sugar moiety, “d” represents a 2′-β-D-deoxyribosyl sugar moiety, “r” represents a β-D-ribosyl sugar moiety, “[f2bDx]” represents a 2′-fluoro-β-D-xylosyl sugar moiety, “[16C 2 r]” represents a 2′-O-hexadecyl-β-D-ribosyl sugar moiety, “[F-HNA]” represents 3′-fluoro-hexitol sugar surrogate, “[bDdx]” represents a 2′-β-D-deox

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Prakash Thazha P
• Oestergaard Michael
• Nikan Mehran
• Freestone Graeme C
• Migawa Michael T
• Anderson Brooke A
• Seth Punit P
• Swayze Eric E

Classifications

• C12N2310/343

  having patterns, e.g. ==--==--==-- · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/314

  Phosphoramidates · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title