Compositions and methods for inhibiting LPA expression
Oligonucleotides are provided herein that inhibit apolipoprotein(a) (LPA) expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with LPA expression.
1. A method for treating a subject having a disease, disorder or condition associated with increased LPA expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand is:
(SEQ ID NO: 793)
5′-[MePhosphonate-40-mUs][fAs][fGs][fA][fU][mG]
[fA][mC][mC][fA][mA][mG][mC][fU][mU][mG][mG][mC]
[mA][mAs][mGs][mG]-3′, and
the sense strand is:
(SEQ ID NO: 393)
5′-[mUs][mU][mG][mC][mC][mA][mA][fG][fC][fU][fU]
[mG][mG][mU][mC][mA][mU][mC][mU][mA][mG][mC][mA]
[mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc]
[ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′,
wherein:
mA represents 2′-OMe adenosine;
mC represents 2′-OMe cytosine;
mG represents 2′-OMe guanosine;
mU represents 2′-OMe uridine;
fA represents 2′-F adenosine;
fC represents 2′-F cytosine;
fG represents 2′-F guanosine;
fU represents 2′-F uridine;
fAs represents 2′-F adenosine with a 3′-phosphorothioate linkage;
fGs represents 2′-F guanosine with a 3′-phosphorothioate linkage;
mAs represents 2′-OMe adenosine with a 3′-phosphorothioate linkage;
mGs represents 2′-OMe guanosine with a 3′-phosphorothioate linkage;
mUs represents 2′-OMe uridine with a 3′-phosphorothioate linkage;
ademA-GalNAc represents 2′-aminodiethoxymethanol-adenine-GalNAc:
and
MePhosphonate-40-mUs represents
thereby treating the subject.
2. A method for reducing LPA expression in a subject, the method comprising the step of:
administering to the subject an RNAi oligonucleotide, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand is:
(SEQ ID NO: 793)
5′-[MePhosphonate-40-mUs][fAs][fGs][fA][fU][mG]
[fA][mC][mC][fA][mA][mG][mC][fU][mU][mG][mG][mC]
[mA][mAs][mGs][mG]-3′, and
the sense strand is:
(SEQ ID NO: 393)
5′-[mUs][mU][mG][mC][mC][mA][mA][fG][fC][fU][fU]
[mG][mG][mU][mC][mA][mU][mC][mU][mA][mG][mC][mA]
[mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc]
[ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′,
wherein:
mA represents 2′-OMe adenosine;
mC represents 2′-OMe cytosine;
mG represents 2′-OMe guanosine;
mU represents 2′-OMe uridine;
fA represents 2′-F adenosine;
fC represents 2′-F cytosine;
fG represents 2′-F guanosine;
fU represents 2′-F uridine;
fAs represents 2′-F adenosine with a 3′-phosphorothioate linkage;
fGs represents 2′-F guanosine with a 3′-phosphorothioate linkage;
mAs represents 2′-OMe adenosine with a 3′-phosphorothioate linkage;
mGs represents 2′-OMe guanosine with a 3′-phosphorothioate linkage;
mUs represents 2′-OMe uridine with a 3′-phosphorothioate linkage;
ademA-GalNAc represents 2′-aminodiethoxymethanol-adenine-GalNAc:
and MePhosphonate-40-mUs represents
3. The method of claim 1 , further comprising the step of reducing LPA expression, and wherein the reducing LPA expression comprises reducing an amount or level of LPA mRNA, an amount or level of apolipoprotein(a) (apo(a)), an amount or level of apo(a) activity, an amount or level of lipoprotein(a) (Lp(a)), or a combination thereof.
4. The method of claim 1 , wherein LPA expression is reduced in the subject by about 75% when compared to LPA expression prior to the administering or when compared to LPA expression in a reference or control subject.
5. The method of claim 1 , wherein an amount or level of cholesterol is reduced in the subject following the administering, and wherein the cholesterol is selected from the group consisting of total cholesterol, LDL cholesterol and HDL cholesterol.
6. The method of claim 1 , wherein an amount or level of apolipoprotein B (ApoB-100) is reduced in the subject following the administering.
7. The method of claim 1 , wherein the disease, disorder or condition associated with increased LPA expression is selected from the group consisting of cardiometabolic diseases, atherosclerosis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
8. The method of claim 1 , wherein the subject is treated therapeutically.
9. The method of claim 1 , wherein the subject is treated prophylactically.
10. The method of claim 1 , wherein the administering comprises a subcutaneous injection.
11. The method of claim 1 , further comprising the step of administering to the subject a second composition or therapeutic agent.
12. The method of claim 1 , wherein LPA expression is reduced in the subject by at least 75% when compared to LPA expression prior to the administering or when compared to LPA expression in a reference or control subject.
13. The method of claim 2 , wherein the reducing LPA expression comprises reducing an amount or level of LPA mRNA, an amount or level of apolipoprotein(a) (apo(a)), an amount or level of apo(a) activity, an amount or level of lipoprotein(a) (Lp(a)), or a combination thereof.
14. The method of claim 2 , wherein LPA expression is reduced in the subject by about 75% when compared to LPA expression prior to the administering or when compared to LPA expression in a reference or control subject.
15. The method of claim 2 , wherein LPA expression is reduced in the subject by at least 75% when compared to LPA expression prior to the administering or when compared to LPA expression in a reference or control subject.
16. The method of claim 2 , wherein an amount or level of cholesterol is reduced in the subject following the administering, and wherein the cholesterol is selected from the group consisting of total cholesterol, LDL cholesterol and HDL cholesterol.
17. The method of claim 2 , wherein an amount or level of apolipoprotein B (ApoB-100) is reduced in the subject following the administering.
18. The method of claim 2 , wherein the subject has a disease, disorder or condition associated with increased LPA expression selected from the group consisting of cardiometabolic diseases, atherosclerosis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
19. The method of claim 2 , wherein the subject is treated therapeutically.
20. The method of claim 2 , wherein the subject is treated prophylactically.
21. The method of claim 2 , wherein the administering comprises a subcutaneous injection.
22. The method of claim 2 , further comprising the step of administering to the subject a second composition or therapeutic agent.