NUCLEIC ACID MOLECULE FOR REDUCTION OF PAPD5 AND PAPD7 mRNA FOR TREATING HEPATITIS B INFECTION

Patent metadata

Field	Value
Publication number	US-2019111073-A1
Application number	US-201816162279-A
Country	US
Kind code	A1
Filing date	Oct 16, 2018
Priority date	Oct 16, 2017
Publication date	Apr 18, 2019
Grant date	—

Abstract

The present invention relates to nucleic acid molecules that are complementary to both PAP associated domain containing 5 (PAPD5) and PAP associated domain containing 7 (PAPD7), leading to inhibition of the expression of both PAPD5 and PAPD7 when using a single nucleic acid molecule. The invention also provides for PAPD5 and PAPD7 specific nucleic acid molecules for use in treating and/or preventing a HBV infection, in particular a chronic HBV infection. Also comprised in the present invention is a pharmaceutical composition for use in the treatment and/or prevention of a HBV infection.

First claim

1 . An antisense oligonucleotide of 12 to 30 nucleotides in length, which comprises a contiguous nucleotide sequence of 12 to 20 nucleotides in length which is capable of inhibiting the expression of both PAPD5 and PAPD7.

2 . The nucleic acid molecule of claim 1 , wherein the contiguous nucleotide sequence is at least 93% complementarity to the target nucleic acid of SEQ ID NO: 1 and SEQ ID NO: 2.

3 . The nucleic acid molecule of claim 1 , wherein the contiguous nucleotide sequence is complementary to position 64669 to 69429 on SEQ ID NO: 1 and position 29514 to 29530 on SEQ ID NO: 2.

4 . The nucleic acid molecule of claim 1 , wherein the contiguous nucleotide sequence is complementary to position 69414 to 69429 on SEQ ID NO: 1 and position 30731 to 30746 on SEQ ID NO: 2.

5 . The antisense oligonucleotide of claim 1 , wherein the contiguous nucleotide sequence comprises or consists of SEQ ID NO: 17 or 18.

6 . The antisense oligonucleotide of claim 1 , comprising one or more 2′ sugar modified nucleoside(s).

7 . The antisense oligonucleotide of claim 5 , wherein the one or more 2′ sugar modified nucleosides is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides.

8 . The antisense oligonucleotide of claim 5 , wherein the one or more 2′ sugar modified nucleosides is a LNA nucleoside.

9 . The antisense oligonucleotide of claim 7 , wherein the LNA nucleoside is oxy-LNA, or cET.

10 . The antisense oligonucleotide of claim 1 , wherein at least 75% of the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages.

11 . The antisense oligonucleotide of claim 10 , wherein at least one of the phosphorothioate internucleoside linkages are stereodefined.

12 . The antisense oligonucleotide of claim 1 , wherein the oligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where the F and F′ wing regions independently comprise 1-8 2′ sugar modified nucleosides and G is a gap region between 5 and 16 nucleosides which are capable of recruiting RNaseH.

13 . The antisense oligonucleotide of claim 12 , wherein
a. the F region is between 1 and 6 nucleotides in length and consists of 1-5 identical LNA nucleosides and 0-3 DNA nucleosides; and b. the F′ region is between 2 and 6 nucleotides in length and consists of 2-5 identical LNA nucleosides and 0-3 DNA nucleosides; and c. the G region consists of between 5 and 11 DNA nucleotides.

14 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is selected from the group consisting of CMP ID NO: 18_1, 18_5, 18_10, 18_15, 18_18, 18_19, 18_24, 18_27, 18_30, 18_346, 18_347, 18_357, 17_10, 17_137 and 17_139.

15 . A conjugate compound comprising the antisense oligonucleotide according to claim 1 and at least one conjugate moiety covalently attached to said oligonucleotide.

16 . The conjugate compound of claim 15 , wherein the conjugate moiety is selected from one of the trivalent GalNAc moieties in FIG. 1 .

17 . The conjugate compound of claim 15 , wherein the conjugate moiety is the trivalent GalNAc moiety in FIG. 1D .

18 . The conjugate compound of claim 15 , comprising a linker positioned between the antisense oligonucleotide and the conjugate moiety.

19 . The conjugate compound of claim 18 , wherein the linker is a physiologically labile linker composed of 2 to 5 consecutive phosphodiester linked nucleosides at the 5′ or 3′ terminal of the contiguous nucleotide sequence of the antisense compound.

20 . The conjugate compound of claim 15 , wherein the conjugate compound is selected from the group consisting of CMP ID NO: 20_12, 20_13, 20_14, 20_15, 20_16, 20_18, 20_20, 20_21, 20_22, 20_30, 20_35, 20_36, 21_2, 21_33 and 21_34.

21 . A pharmaceutical composition comprising the antisense oligonucleotide according to claim 1 and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.

22 . An in vivo or in vitro method for modulating PAPD5 and PAPD7 expression in a target cell which is expressing PAPD5 and PAPD7, said method comprising administering an antisense oligonucleotide according to claim 1 in an effective amount to said cell.

23 . The antisense oligonucleotide according to claim 1 for use as a medicament.

24 . The antisense oligonucleotide according to claim 1 , for use in the treatment or prevention of HBV infection or chronic HBV infection or reduction of the infectiousness of a HBV infected person.

25 . A pharmaceutical composition comprising the conjugate compound of claim 15 or acceptable salts thereof, and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.

26 . An in vivo or in vitro method for modulating PAPD5 and PAPD7 expression in a target cell which is expressing PAPD5 and PAPD7, said method comprising administering the conjugate compound of claim 15 in an effective amount to said cell.

27 . The conjugate compound of claim 15 for use as a medicament.

28 . The pharmaceutical composition of claim 21 for use as a medicament.

29 . The antisense oligonucleotide according to claim 1 for use in the treatment or prevention of HBV infection or chronic HBV infection or reduction of the infectiousness of a HBV infected person.

30 . The conjugate compound of claim 15 for use in the treatment or prevention of HBV infection or chronic HBV infection or reduction of the infectiousness of a HBV infected person.

31 . The pharmaceutical composition of claim 21 for use in the treatment or prevention of HBV infection or chronic HBV infection or reduction of the infectiousness of a HBV infected person.

Assignees

• Hoffmann La Roche
• Roche Innovation Ct Copenhagen As

Inventors

• Kammler Susanne
• Lopez Anaïs
• Mueller Henrik
• Ottosen Søren
• Pedersen Lykke

Classifications

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/3231

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

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/351

  Conjugate · CPC title