Modified oligonucleotides and methods of use

1. A chimeric antisense oligonucleotide represented by Formula (A):

5′X—Y—Z 3′  (A),

wherein

X—Y—Z is a chimeric oligonucleotide comprising a sequence of 18 to 22 nucleosides, optionally conjugated at the 5′ and/or 3′ end to a ligand targeting group;

X is a domain comprising a sequence of modified nucleosides that is 3-10 nucleosides in length;

Z is a domain comprising a sequence of modified nucleosides that is 3-10 nucleosides in length; and

Y is a domain comprising a sequence of 2 to 10 2′-deoxy-nucleosides linked through thiophosphate intersubunit linkages,

wherein each modified nucleoside in the X domain and each modified nucleoside in the Z domain are nucleosides of Formula (1)

wherein

R is H or a positively charged counter ion,

B is a nucleobase,

R 1 is —(CR′ 2 ) 2 OCR′ 3 or -OEt, and

R′ is independently in each instance H or F; and

wherein said oligonucleotide is complementary to a sequence of the HBV genome.

2. The oligonucleotide of claim 1 , wherein

R is H,

R 1 is —(CR′ 2 ) 2 OCR′ 3 , and

each R′ is H.

3. The oligonucleotide of claim 1 , wherein the X domain and the Z domain each comprise a sequence of modified nucleosides that is 4-6 nucleosides in length.

4. The oligonucleotide of claim 1 , wherein R 1 is -OEt.

5. The oligonucleotide of claim 1 , wherein R 1 is —(CH 2 ) 2 OCH 3 .

6. The oligonucleotide of claim 1 , wherein the Y domain sequence comprises 10 nucleosides.

7. The oligonucleotide of claim 6 , wherein the Y domain comprises a nucleobase sequence of GGTGAAG(5m)CGA (SEQ ID NO: 576).

8. The oligonucleotide of claim 6 , wherein the X domain and the Z domain each comprise a sequence of modified nucleosides that is 5 nucleosides in length.

9. The oligonucleotide of claim 1 , wherein the ligand targeting group comprises a GalNAc moiety.

10. A pharmaceutical composition comprising an oligonucleotide of claim 1 and a pharmaceutically acceptable excipient.