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 method of inhibiting the expression of apolipoprotein(a) in a cell or tissue in vivo, said method comprising contacting said cell or tissue with an antisense oligonucleotide 12 to 30 nucleobases in length targeted to SEQ ID NO: 4, wherein said antisense oligonucleotide comprises at least 8 consecutive nucleobases of SEQ ID NO: 23 and is 100% complementary to SEQ ID NO: 4, thereby inhibiting the expression of apolipoprotein(a).
2. The method of claim 1 , wherein said antisense oligonucleotide is a chimeric antisense oligonucleotide.
3. The method of claim 1 , wherein said antisense oligonucleotide comprises at least one modified internucleoside linkage, modified sugar moiety, or modified nucleobase.
4. The method of claim 3 , wherein said modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.
5. The method of claim 3 , wherein said modified internucleoside linkage is a phosphorothioate internucleoside linkage.
6. The method of claim 3 , wherein said modified nucleobase is a 5-methylcytosine.
7. A method of treating a human having a disease or condition treatable by the reduction of apolipoprotein(a), said method comprising
selecting a human having elevated plasma lipoprotein(a) levels; and
administering to said human a therapeutically effective amount of an antisense oligonucleotide 12 to 30 nucleobases in length targeted to SEQ ID NO: 4, wherein said antisense oligonucleotide comprises at least 8 consecutive nucleobases of SEQ ID NO: 23 and is 100% complementary to SEQ ID NO: 4.
8. The method of claim 7 , wherein the disease or condition is atherosclerosis or hypercholesterolemia.
9. The method of claim 7 , wherein said antisense oligonucleotide is a chimeric antisense oligonucleotide.
10. The method of claim 7 , wherein said antisense oligonucleotide comprises at least one modified internucleoside linkage, modified sugar moiety, or modified nucleobase.
11. The method of claim 10 , wherein said modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.
12. The method of claim 10 , wherein said modified internucleoside linkage is a phosphorothioate internucleoside linkage.
13. The method of claim 10 , wherein said modified nucleobase is a 5-methylcytosine.
14. The method of claim 7 , further comprising measuring lipoprotein(a) levels in the serum of said human following said administering.
15. The method of claim 8 , wherein said chimeric antisense oligonucleotide comprises a gap segment of ten 2′-deoxynucleotides positioned between 5′ and 3′ wing segments of five 2′-O-methoxyethyl modified nucleosides.
16. The method of claim 15 , wherein each intemucleoside linkage of said chimeric antisense oligonucleotide is a phosphorothioate internucleoside linkage.
17. The method of claim 16 , wherein each cytosine of said chimeric antisense oligonucleotide is a 5-methylcytosine.
18. The method of claim 1 , wherein said antisense oligonucleotide has a nucleobase sequence comprising SEQ ID NO: 23.
19. The method of claim 1 , wherein said antisense oligonucleotide consists of SEQ ID NO: 23.
20. The method of claim 9 , wherein said chimeric antisense oligonucleotide comprises a gap segment of ten 2′-deoxynucleotides positioned between 5′ and 3′ wing segments of five 2′-O-methoxyethyl modified nucleosides.
21. The method of claim 20 , wherein each internucleoside linkage of said chimeric antisense oligonucleotide is a phosphorothioate internucleoside linkage.
22. The method of claim 21 , wherein each cytosine of said chimeric antisense oligonucleotide is a 5-methylcytosine.
23. The method of claim 7 , wherein said antisense oligonucleotide has a nucleobase sequence comprising SEQ ID NO: 23.
24. The method of claim 7 , wherein said antisense oligonucleotide consists of SEQ ID NO: 23.
25. The method of claim 1 , wherein said antisense oligonucleotide consists of SEQ ID NO: 23, wherein nucleotides 1–5 and 16–20 are 2′-O-methoxyethyl nucleotides, wherein nucleotides 6–15 are 2′-deoxynucleotides, and wherein each cytosine is a 5-methylcytosine.
26. The method of claim 7 , wherein said antisense oligonucleotide consists of SEQ ID NO: 23, wherein nucleotides 1–5 and 16–20 are 2′-O-methoxyethyl nucleotides, wherein nucleotides 6–15 are 2′-deoxynucleotides, and wherein each cytosine is a 5-methylcytosine.