US 2025/0376684 A1 · THREOSE NUCLEIC ACID ANTISENSE OLIGONUCLEOTIDES AND METHODS THEREOF

Abstract

Described are antisense oligonucleotides comprising one or more α-L-threofuranosyl (TNA) nucleosides linked to an adjacent nucleoside via a phosphodiester (PO) internucleoside linkage, as well as methods to modulate the properties of antisense oligonucleotides by the introduction of such TNA nucleosides. These are particularly applicable to antisense gapmer oligonucleotides.

Claims20

Dependent claims

An antisense gapmer oligonucleotide comprising a contiguous nucleotide sequence of formula 5′-F-G-F′-3′ (I) which is capable of recruiting ribonuclease (RNase) H, wherein

G is a gap region of up to 18 linked nucleosides which comprises at least 3 contiguous DNA nucleosides,
each of F and F′ is a flanking region of up to 15 linked nucleosides which independently comprises or consists of 1 to 15 sugar-modified nucleosides,
at least one of F, F′ and G comprises a sugar-modified nucleoside which is an α-L-threofuranosyl (TNA) nucleoside and which is linked to an adjacent nucleoside by an internucleoside linkage different than a phosphorothioate (PS) internucleoside linkage.

The antisense gapmer oligonucleotide according to any one of the preceding claims, wherein the sugar-modified nucleosides of F, F′ or both F and F′, comprise at least one sugar-modified nucleoside comprising a modified sugar-moiety selected from the group consisting of:

α-L-threofuranosyl (as in threose nucleic acid;
TNA),
2′-methoxy-ribose (2′-OMe),
2′-O-methoxyethyl-ribose (2′-O-MOE),
5′-methyl-2′-O-methoxyethyl ribose (5′-Me-2′-O-MOE),
2′-O-[2-(methylthio)ethyl]-ribose (2′-O-MTE),
2-(N-methylcarbamoyl)-ethyl]-ribose (2′-O-MCE),
2′-O-[2-(methylamino)-2-oxoethyl]-ribose (2′-O-NMA),
2′-deoxy-2′-fluoro-ribose (as in 2′-deoxy-2′-fluororibo-nucleic acid;
2′-F-RNA),
2′-fluoro-2′-arabinose (as in 2′-fluoro-2′-arabinose nucleic acid;
2′-F-ANA),
2′-O-benzyl-ribose,
oxy β-D-locked ribose (as in β-D-LNA),
amino β-D-locked ribose (as in amino-β-D-LNA),
thio β-D-locked ribose (as in thio-β-D-LNA),
oxy β-L-locked ribose (as in β-L-LNA),
amino β-L-locked ribose (as in amino-β-L-LNA),
thio β-L-locked ribose (as in thio-β-L-LNA),
oxy α-L-locked ribose (as in α-L-LNA),
amino α-L-locked ribose (as in amino-α-L-LNA),
thio α-L-locked ribose (as in thio-α-L-LNA),
2′,4′-constrained 2′-O-ethyl ribose (as in constrained ethyl locked nucleic acid;
cEt),
tricyclo-deoxyribose (as in tricyclo-deoxyribose DNA;
TcDNA),
3′-deoxy-ribose (as in 3′-deoxy-ribose DNA;
3′-DNA),
unlocked ribose (as in unlocked nucleic acid;
UNA),
glycol (as in glycol nucleic acid;
GNA),
hexitol (as in hexitol nucleic acid;
HNA),
3′-fluoro hexitol (as in 3′-fluoro hexitol nucleic acid;
FHNA),
3′-arabino-fluoro hexitol (as in 3′-arabino-gluoro hexitol nucleic acid;
Ara-FHNA),
cyclohexene (as in cyclohexene nucleic acid;
CeNA),
fluoro-cyclohexenenyl (as in 2′-fluoro-cyclohexenyl nucleic acid;
F-CeNA),
serinol (as in serinol nucleic acid;
SNA),
2′-O,4′-C-ethylene bridged ribose (as in 2′-O,4′-C-ethylene linked nucleic acid;
ENA)
acyclic (L)-threoninol (as in acyclic (L)-threoninol nucleic acid;
aTNA)
2′,4′-constrained 2′-O-methoxyethyl ribose (as in cMOE)
7′,5′-alpha-bicyclo sugar unit (as in 7′,5′-alpha-bicyclo DNA;
bcDNA).

48 more elements

Dependencies are inferred from the claim text.

Threose nucleic acid antisense oligonucleotides and methods thereof

Life of this patent

Threose nucleic acid antisense oligonucleotides and methods thereof

Life of this patent

Abstract

Claims20