Compositions and methods for inhibiting gene expression of LPA
RNA interference (RNAi) agents and RNAi agent conjugates for inhibiting the expression of the LPA (apo(a)) gene are described. Pharmaceutical compositions comprising one or more LPA RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described LPA RNAi agents to liver cells in vivo provides for inhibition of LPA gene expression and treatment of cardiovascular and cardiovascular-related diseases.
1. An LPA RNA interference (RNAi) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a core sequence that is complementary to an LPA mRNA sequence, said core sequence comprising the sequence of SEQ ID NO: 1280, and wherein the sense strand comprises a sequence that is complementary to the core sequence of the antisense strand.
2. The LPA RNAi agent of claim 1 , wherein the sense strand and antisense strand are each 19 to 26 nucleotides in length.
3. The LPA RNAi agent of claim 2 , wherein the sense strand and antisense strand are each 26 nucleotides in length.
4. The LPA RNAi agent of claim 2 , wherein the sense strand and antisense strand are each 21 nucleotides in length.
5. The LPA RNAi agent of claim 1 , wherein the LPA RNAi agent comprises at least one overhang.
6. The LPA RNAi agent of claim 5 , wherein the LPA RNAi agent comprises an overhang at the 3′ end of the antisense strand.
7. The LPA RNAi agent of claim 5 , wherein the LPA RNAi agent comprises an overhang at the 3′ end of the antisense strand and an overhang at the 3′ end of the sense strand.
8. The LPA RNAi agent of claim 1 , wherein the LPA RNAi agent comprises at least one blunt end.
9. The LPA RNAi agent of claim 8 , wherein the LPA RNAi agent comprises one blunt end and one frayed end.
10. The LPA RNAi agent of claim 8 , wherein the LPA RNAi agent comprises two blunt ends.
11. The LPA RNAi agent of claim 1 , wherein the sense strand, the antisense strand, or both the sense and antisense strand comprise one or more modified nucleotides.
12. The LPA RNAi agent of claim 11 , wherein the one or more modified nucleotides are independently selected from a 2′-modified nucleotide, a locked nucleotide, an abasic nucleotide, an inverted deoxynucleotide, a morpholino nucleotide, a 2′,3′-seco nucleotide mimic, or a nucleotide containing a non-natural base.
13. The LPA RNAi agent of claim 12 , wherein the 2′-modified nucleotide is a 2′-O-methyl nucleotide, a 2′-deoxy-2′-fluoro nucleotide, a 2′-deoxynucleotide, a 2′-methoxyethyl nucleotide, a 2′-amino nucleotide, or a 2′-alkyl nucleotide.
14. The LPA RNAi agent of claim 1 , wherein the LPA RNAi agent comprises one or more phosphorothioate internucleoside linkages.
15. The LPA RNAi agent of claim 14 , wherein both the sense and antisense strand independently comprise 1, 2, 3, or 4 phosphorothioate internucleoside linkages.
16. The LPA RNAi agent of claim 1 , wherein the LPA RNAi agent further comprises a targeting group.
17. The LPA RNAi agent of claim 16 , wherein the targeting group comprises an asialoglycoprotein receptor ligand.
18. The LPA RNAi agent of claim 17 , wherein the asialoglycoprotein receptor ligand comprises galactose, galactosamine, N-acetyl-galactosamine, or a galactose derivative.
19. The LPA RNAi agent of claim 16 , wherein the targeting group is (Chol-TEG), (TEG-Chol), (C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG3), (NAG4), (NAG3-AA2), (NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27) (NAG28) (NAG29) (NAG30) (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), or (NAG37).
20. The LPA RNAi agent of claim 16 , wherein the targeting group is conjugated to the 3′ end of the sense strand.
21. The LPA RNAi agent of claim 16 , wherein the targeting group is conjugated to the 5′ end of the sense strand.
22. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises a sequence selected from SEQ ID NO: 6, SEQ ID NO: 111, SEQ ID NO: 156, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 164, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 1242, or SEQ ID NO: 1282.
23. The LPA RNAi agent of claim 1 , wherein the sense strand comprises the sequence of SEQ ID NO: 1284.
24. The LPA RNAi agent of claim 23 , wherein the sense strand comprises a sequence selected from SEQ ID NO: 195, SEQ ID NO: 270, SEQ ID NO: 310, SEQ ID NO: 354, SEQ ID NO: 355, SEQ ID NO: 357, SEQ ID NO: 358, SEQ ID NO: 359, SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 366, SEQ ID NO: 371, SEQ ID NO: 372, SEQ ID NO: 373, SEQ ID NO: 375, SEQ ID NO: 376, SEQ ID NO: 377, SEQ ID NO: 378, SEQ ID NO: 379, SEQ ID NO: 380, SEQ ID NO: 381, SEQ ID NO: 383, SEQ ID NO: 384, SEQ ID NO: 1243, SEQ ID NO: 1259, SEQ ID NO: 1260, or SEQ ID NO: 1261.
25. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 156 and the sense strand comprises the sequence of SEQ ID NO: 310.
26. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 164 and the sense strand comprises the sequence of SEQ ID NO: 357.
27. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 188 and the sense strand comprises the sequence of SEQ ID NO: 384.
28. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 164 and the sense strand comprises the sequence of SEQ ID NO: 376.
29. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 164 and the sense strand comprises the sequence of SEQ ID NO: 384.
30. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 790 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1189.
31. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 637 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1132.
32. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 709 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1135.
33. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 787 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1191.
34. The LPA RNAi agent of claim 1 , wherein the antisense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 788 and the sense strand comprises the sequence of modified nucleotides according to SEQ ID NO: 1189.
35. A pharmaceutical composition comprising the LPA RNAi agent of claim 1 and a pharmaceutically acceptable excipient.
36. A method for inhibiting LPA gene expression in a subject comprising administering to the subject the LPA RNAi agent of claim 1 .
37. The method of claim 36 , wherein the subject has or is at risk of having cardiovascular disease.
38. A method for treating cardiovascular disease in a subject in need thereof comprising administering to the subject an effective amount of the LPA RNAi agent of claim 1 .
39. The method of claim 38 , wherein the effective amount is sufficient to reduce the apo(a) expression level in the subject by at least about 40% relative to the subject's apo(a) expression level prior to administration of the LPA RNAi agent.