Methods and compositions for modulating apolipoprotein (a) expression

Patent metadata

Field	Value
Publication number	US-9574193-B2
Application number	US-201414552436-A
Country	US
Kind code	B2
Filing date	Nov 24, 2014
Priority date	May 17, 2012
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Disclosed herein are antisense compounds and methods for decreasing apo(a) to treat, prevent, or ameliorate diseases, disorders or conditions related to apo(a) or Lp(a). Certain diseases, disorders or conditions related to apo(a) or Lp(a) include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The antisense compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.

First claim

The invention claimed is:

1. A method of lowering apo(a) and/or Lp(a) levels in a subject, comprising:
administering to said subject a compound comprising a modified oligonucleotide, wherein:
the modified oligonucleotide consists of 14 to 25 linked nucleosides and comprises a nucleobase sequence comprising a portion of at least 14 contiguous nucleobases complementary to an equal length portion of nucleobases 3900 to 3923 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1, or a salt thereof, whereby apo(a) and/or Lp(a) levels are reduced in the animal subject.

2. The method of claim 1 , wherein the subject has elevated apo(a) and/or Lp(a) levels or a condition associated with elevated apo(a) and/or Lp(a) levels.

3. The method of claim 1 , wherein apo(a) mRNA and/or protein levels are lowered.

4. The method of claim 1 , wherein the modified oligonucleotide consists of 18 to 24, 19 to 22, 15 to 25, 16 or 20 linked nucleosides.

5. The method of claim 1 , wherein the modified oligonucleotide comprises a nucleobase sequence comprising a portion of at least 16, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 1.

6. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 96%, 97%, 98% or 99% complementary to SEQ ID NO: 1, or is 100% complementary to SEQ ID NO: 1.

7. The method of claim 1 , wherein the modified oligonucleotide consists of 14 to 25 linked nucleosides and comprises a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 58.

8. The method of claim 1 , wherein the modified oligonucleotide is single-stranded.

9. The method of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.

10. The method of claim 9 , wherein the at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

11. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.

12. The method of claim 11 , wherein at least one modified sugar is a bicyclic sugar.

13. The method of claim 11 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.

14. The method of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.

15. The method of claim 14 , wherein the modified nucleobase is a 5-methylcytosine.

16. The method of claim 1 , wherein the modified oligonucleotide consists of 14 to 25 linked nucleosides and comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

17. The method of claim 16 , wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein at least one internucleoside linkage is a modified internucleoside linkage and wherein each cytosine residue is a 5-methylcytosine.

18. The method of claim 16 , wherein the modified oligonucleotide consists of 20 linked nucleosides.

19. The method of claim 1 , wherein the modified oligonucleotide consists of 20 contiguous linked nucleosides of SEQ ID NO: 58 and the modified oligonucleotide further comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein at least one internucleoside linkage is a modified internucleoside linkage and wherein each cytosine residue is a 5-methylcytosine.

20. The method of claim 1 , wherein a therapeutically effective dose of the modified oligonucleotide is administered, whereby a disease associated with elevated apo(a) and/or elevated Lp(a) levels in the subject is treated, its onset delayed, the progression slowed or a symptom ameliorated.

21. The method of claim 20 , wherein the disease is an inflammatory, cardiovascular or metabolic disorder or condition.

22. The method of claim 1 , wherein the subject is a human subject.

23. The method of claim 1 , wherein the compound is a first agent and is co-administered with one or more secondary agents or therapy.

24. The method of claim 1 , wherein the modified oligonucleotide has a viscosity of less than 40 cP.

25. The method of claim 23 , wherein the one or more secondary agents or therapy is/are selected from among an apo(a) lowering agent, a Lp(a) lowering agent, an agent to reduce thromboembolism formation, a glucose-lowering agent, a LDL lowering agent, a triglyceride lowering agent, a cholesterol lowering agent, a HDL raising agent, an anti-inflammatory agent, an Alzheimer Disease drug, a non-steroidal anti-inflammatory drug (NSAID), fish oil, niacin, nicotinic acid, an apoB inhibitor, a CETP inhibitor, a thyroid hormone analog, a HMG-CoA reductase inhibitor, a fibrate, a microsomal triglyceride transfer protein inhibitor and Lp(a) apheresis.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Crooke Rosanne M
• Graham Mark J
• Freier Susan M
• Lim Marc
• Dibble Andrew

Classifications

• A61K31/7115 Primary

  Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• 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

• C12N2310/321

  2'-O-R Modification · CPC title

• A61K31/7125

  Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters · CPC title