Potent anti APOB antisense compounds

Patent metadata

Field	Value
Publication number	US-9290758-B2
Application number	US-201013140777-A
Country	US
Kind code	B2
Filing date	Jun 14, 2010
Priority date	Jun 12, 2009
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

The present invention relates to oligomer compounds (oligomers), which target APO-B100 mRNA in a cell, leading to reduced expression of APO-B100. Reduction of APO-B100 expression is beneficial for the treatment of certain medical disorders, such as diseases associated with apolipoproteinB activity, such as in non-limiting example, different types of HDL/LDL cholesterol imbalance; dyslipidemias, e.g., familial combined dyslipidemia (FCHL), acquired hyperlipidemia, hypercholesterolemia, statin-resistant hypercholesterolemia; coronary artery disease (CAD), coronary heart disease (CHD), atherosclerosis.

First claim

The invention claimed is:

1. A single stranded oligomer of 12-18 nucleotides comprising a contiguous nucleotide sequence that is at least 90% identical SEQ ID NO:4 wherein the oligomer has six contiguous DNA nucleobases and at least two locked nucleic acids (LNA).

2. The single stranded oligomer of claim 1 wherein the contiguous nucleotide sequence is identical to SEQ ID NO:4.

3. The single stranded oligomer of claim 1 having 12-16 nucleotides.

4. The single stranded oligomer of claim 1 comprising one or more phosphothioate internucleotide linkages.

5. The single stranded oligomer of claim 1 wherein at least one of the LNA is an oxy-LNA.

6. The single stranded oligomer of claim 5 wherein at least one of the LNA is a methyl C-LNA.

7. The single stranded oligomer of claim 1 comprising SEQ ID NO:28 or SEQ ID NO:29.

8. A pharmaceutical composition comprising the single stranded oligomer of claim 1 .

9. A method of treating a disorder selected from: example, different types of HDL/LDL cholesterol imbalance, dyslipidemia, acquired hyperlipidemia, hypercholesterolemia, statin-resistant hypercholesterolemia, coronary artery disease (CAD), coronary heart disease (CHD) and atherosclerosis, the method comprising administering to a patient and the single stranded oligomer of claim 1 .

10. The single stranded oligomer of claim 1 having the formula
A-B-C,
wherein:
A comprises 1-4 LNA nucleotides:
B comprises 6-12 consecutive DNA nucleotides; and
C comprises 1-4 LNA nucleotides.

11. The single stranded oligomer of claim 10 having 12-16 nucleotides.

12. The single stranded oligomer of claim 10 , wherein:
A consists of 2 or 3 LNA nucleotides;
B consists of 8-10 consecutive DNA nucleotides; and
C consists of 2 or 3 LNA nucleotides.

13. The singled stranded oligomer of claim 1 having 12 nucleotides.

14. The single stranded oligomer of claim 10 , wherein:
A consists of 2 LNA nucleotides;
B consists of 8 contiguous DNA nucleotides; and
C consists of 2 LNA nucleotides.

15. The single stranded oligomer of claim 1 having the formula
5′-G s T s t s g s a s c s a s c s t s g s T s m C-3′  (SEQ ID NO:29)

wherein capital letters represent LNA nucleobases, lower case letters represent DNA nucleotides, subscript s represent a phosphorothioate internucleoside linkage, and superscript m preceding a capital C indicates a 5-methyl cytosine LNA.

16. A pharmaceutical composition comprising the single stranded oligomer of claim 5 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the single stranded oligomer of claim 15 and a pharmaceutically acceptable carrier.

18. The single stranded oligomer of claim 2 , wherein all internucleotide linkages are phosphothioate internucleotide linkages.

Assignees

• Nielsen Niels Fisker
• Straarup Ellen Marie
• Lindholm Marie Wickstrom
• Roche Innovation Ct Copenhagen As

Inventors

• Nielsen Niels Fisker
• Straarup Ellen Marie
• Lindholm Marie Wickstrom

Classifications

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C12N2310/3231

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