Potent anti APOB antisense compounds
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.
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.