Compounds and methods for the modulation of amyloid-β precursor protein

Patent metadata

Field	Value
Publication number	US-11732260-B2
Application number	US-201916977649-A
Country	US
Kind code	B2
Filing date	Mar 1, 2019
Priority date	Mar 2, 2018
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

Abstract

Certain embodiments disclosed herein are directed to compounds and methods for modulating APP expression. In certain embodiments, modulating the splicing of amyloid precursor protein (APP) reduces amyloid β (Aβ) production.

First claim

The invention claimed is:

1. A modified oligonucleotide consisting of 16 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to an equal-length portion within nucleobase 282128 and nucleobase 282150 of SEQ ID NO: 1, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

2. A modified oligonucleotide consisting of 18 to 21 linked nucleosides, wherein the modified oligonucleotide comprises a nucleobase sequence selected from SEQ ID NOs: 7-10, 13, 14, 16, 19-21, 23, 24, 27, 28, 30-32, and 34-42, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.

3. The modified oligonucleotide of claim 2 , wherein the nucleobase sequence of the modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 39.

4. The modified oligonucleotide of claim 2 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% or is 100% complementary to an equal-length region of SEQ ID NO: 1, as measured over the entire length of the modified oligonucleotide.

5. The modified oligonucleotide of claim 2 , consisting of a single-stranded modified oligonucleotide.

6. The modified oligonucleotide of claim 2 , wherein the modified oligonucleotide comprises at least one modified nucleoside.

7. The modified oligonucleotide of claim 6 , wherein at least one modified nucleoside comprises a modified sugar moiety.

8. The modified oligonucleotide of claim 7 , wherein at least one modified sugar moiety is a 2′-substituted sugar moiety.

9. The modified oligonucleotide of claim 8 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from among: 2′-OMe, 2′-F, and 2′-O-methoxyethyl.

10. The modified oligonucleotide of claim 7 , wherein at least one modified sugar moiety is a bicyclic sugar moiety.

11. The modified oligonucleotide of claim 10 , wherein at least one bicyclic sugar moiety is LNA or cEt.

12. The modified oligonucleotide of claim 7 , wherein at least one sugar moiety is a sugar surrogate.

13. The modified oligonucleotide of claim 12 , wherein at least one sugar surrogate is a morpholino or a modified morpholino.

14. The modified oligonucleotide of claim 2 , wherein the modified oligonucleotide comprises at least 5, at least 10, at least 15, at least 16, at least 17, or 18 modified nucleosides, each independently comprising a modified sugar moiety.

15. The modified oligonucleotide of claim 2 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

16. The modified oligonucleotide of claim 15 , wherein each internucleoside linkage is a modified internucleoside linkage.

17. The modified oligonucleotide of claim 15 , comprising at least one phosphorothioate internucleoside linkage.

18. A pharmaceutical composition comprising a modified oligonucleotide according to claim 2 , and a pharmaceutically acceptable carrier or diluent.

19. A method of modulating splicing of an APP transcript in a cell comprising contacting the cell with a modified oligonucleotide according to claim 2 .

20. The method of claim 19 , wherein inclusion of exon 17 in the APP transcript is reduced.

21. A method of decreasing expression of amyloid β in a cell, comprising contacting the cell with a modified oligonucleotide according to claim 2 .

22. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide consists of 18 linked nucleosides, wherein each internucleoside linkage is a modified internucleoside linkage and each of the nucleosides comprises a 2′-O-methoxyethyl substituted sugar moiety.

23. The modified oligonucleotide of claim 1 , consisting of a single-stranded modified oligonucleotide.

24. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside.

25. The modified oligonucleotide of claim 24 , wherein at least one modified nucleoside comprises a modified sugar moiety.

26. The modified oligonucleotide of claim 25 , wherein at least one modified sugar moiety is a 2′-substituted sugar moiety.

27. The modified oligonucleotide of claim 26 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from among: 2′-OMe, 2′-F, and 2′-O-methoxyethyl.

28. The modified oligonucleotide of claim 25 , wherein at least one modified sugar moiety is a bicyclic sugar moiety.

29. The modified oligonucleotide of claim 28 , wherein at least one bicyclic sugar moiety is LNA or cEt.

30. The modified oligonucleotide of claim 25 , wherein at least one sugar moiety is a sugar surrogate.

31. The modified oligonucleotide of claim 30 , wherein at least one sugar surrogate is a morpholino or a modified morpholino.

32. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least 5, at least 10, at least 15, at least 16, at least 17, or 18 modified nucleosides, each independently comprising a modified sugar moiety.

33. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

34. The modified oligonucleotide of claim 33 , wherein each internucleoside linkage is a modified internucleoside linkage.

35. The modified oligonucleotide of claim 33 , comprising at least one phosphorothioate internucleoside linkage.

36. A pharmaceutical composition comprising a modified oligonucleotide according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

37. A method of modulating splicing of an APP transcript in a cell comprising contacting the cell with a modified oligonucleotide according to claim 1 .

38. The method of claim 37 , wherein inclusion of exon 17 in the APP transcript is reduced.

39. A method of decreasing expression of amyloid β in a cell, comprising contacting the cell with a modified oligonucleotide according to claim 1 .

Assignees

• Ionis Pharmaceuticals Inc
• Univ Rosalind Franklin Medicine & Science

Inventors

• Rigo Frank
• Hastings Michelle L

Classifications

• C12N15/113 Primary

  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 title

• C12N2310/11

  Antisense · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/32

  of the sugar · CPC title

• C12N2310/3231

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