Modulation of apolipoprotein (A) expression
View Patent ↗Compounds, compositions and methods are provided for modulating the expression of apolipoprotein(a). The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein(a). Methods of using these compounds for modulation of apolipoprotein(a) expression and for diagnosis and treatment of disease associated with expression of apolipoprotein(a) are provided.
1. A compound comprising an antisense oligonucleotide 12 to 30 nucleobases in length targeting apolipoprotein(a), wherein said oligonucleotide comprises at least an 8-nucleobase portion of the nucleobase sequence of SEQ ID NO: 11.
2. The compound of claim 1 , wherein said oligonucleotide is 90% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO: 3).
3. The compound of claim 1 , wherein said oligonucleotide is 95% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO: 3).
4. The compound of claim 1 , wherein said oligonucleotide is 20 nucleobases in length.
5. The compound of claim 1 , wherein said oligonucleotide is a chimeric oligonucleotide.
6. The compound of claim 1 , wherein said oligonucleotide comprises at least one modified internucleoside linkage.
7. The compound of claim 6 , wherein the modified internucleoside linkage is a phosphorothioate linkage.
8. The compound of claim 1 , wherein said oligonucleotide comprises at least one modified sugar moiety.
9. The compound of claim 8 , wherein said modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.
10. The compound of claim 1 , wherein said oligonucleotide comprises at least one modified nucleobase.
11. The compound of claim 10 , wherein said modified nucleobase is a 5-methylcytosine.
12. The compound of claim 5 , wherein said chimeric oligonucleotide comprises a gap segment of linked 2′-deoxynucleotides which is flanked on each side by at least one 2′-O-methoxyethyl nucleotide.
13. The compound of claim 12 , wherein said gap segment is ten 2′-deoxynucleotides in length.
14. The compound of claim 12 , wherein said gap segment is flanked on each side by five 2′-O-methoxyethyl nucleotides.
15. A composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.
16. The compound of claim 1 , having at least 12 linked nucleobases of SEQ ID NO: 11.
17. The compound of claim 5 , wherein said oligonucleotide comprises at least one modified internucleoside linkage, wherein the modified internucleoside linkage is a phosphorothioate linkage, wherein said oligonucleotide comprises a gap segment of linked 2′-deoxynucleotides which is flanked on each side by at least one 2′-O-methoxyethyl nucleotide, wherein each cytosine is a 5-methylcytosine, and wherein said oligonucleotide is 95% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO: 3).
18. A compound comprising an antisense oligonucleotide 20 nucleobases in length, wherein said oligonucleotide comprises at least an 8-nucleobase portion of the nucleobase sequence of SEQ ID NO: 11, wherein said oligonucleotide comprises a gap segment of ten linked 2′-deoxynucleotides which is flanked on each side by five 2′-O-methoxyethyl nucleotides, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.