Nucleic acids for inhibiting expression of LPA in a cell

1. A method of treating a cardiovascular disease, disorder or syndrome comprising administering to an individual in need thereof a a nucleic acid or a composition comprising said nucleic acid for inhibiting expression of apolipoprotein(a) (LPA) gene in a cell, said nucleic acid comprising at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to at least a portion of RNA transcribed from the LPA gene,

wherein said first strand is 19-35 nucleotides in length and comprises a nucleotide sequence of SEQ ID NO: 9;

said second strand is 17-35 nucleotides in length and optionally comprises a nucleotide sequence of SEQ ID NO: 10;

and wherein the at least one duplex region consists of 17-25 consecutive nucleotide base pairs.

2. The method according to claim 1 , wherein the cardiovascular disease, disorder, or syndrome is selected from stroke, atherosclerosis, thrombosis, coronary heart disease or aortic stenosis.

3. The method of claim 1 , wherein said second strand comprises a nucleotide sequence of SEQ ID NO: 10.

4. The method of claim 1 , wherein said second strand is 17-25 nucleotides in length.

5. The method of claim 1 , wherein the at least one duplex region consists of 19-25 consecutive nucleotide base pairs.

6. The method of claim 1 , wherein the nucleic acid is blunt ended at both ends.

7. The method of claim 1 , wherein one or more nucleotides on the first and/or second strand are modified, to form modified nucleotides.

8. The method of claim 1 , wherein the nucleic acid is conjugated to a ligand.

9. The method of claim 8 , wherein the ligand comprises (i) one or more N-acetyl galactosamine (GalNAc) moieties or derivatives thereof, and (ii) a linker, wherein the linker conjugates the at least one GalNAc moiety or derivative thereof to the nucleic acid.

10. The method of claim 8 , wherein the nucleic acid is conjugated to a ligand comprising a compound of formula (I):

[S—X 1 —P—X 2 ] 3 -A-X 3 —  (I)

wherein:

S represents a saccharide, preferably wherein the saccharide is N-acetyl galactosamine;

X 1 represents C 3 -C 6 alkylene or (—CH 2 —CH 2 —O) m (—CH 2 ) 2 — wherein m is 1, 2, or 3;

P is a phosphate or modified phosphate, preferably a thiophosphate;

X 2 is alkylene or an alkylene ether of the formula (—CH 2 ) n —O—CH 2 — where n=1-6;

A is a branching unit;

X 3 represents a bridging unit;

wherein the nucleic acid as defined in claim 1 is conjugated to X 3 via a phosphate or modified phosphate, preferably a thiophosphate.

11. The method of claim 8 , wherein the first RNA strand is a compound of formula (X):

wherein b is 0 or 1; and

the second RNA strand is a compound of formula (XI):

wherein:

c and d are independently 0 or 1;

Z 1 and Z 2 are the RNA portions of the first and second RNA strands respectively;

Y is O or S;

n is 0, 1, 2 or 3; and

L 1 is a linker to which a ligand is attached; and

wherein b+c+d is 2 or 3.

12. The method of claim 1 , wherein said first strand consists of the nucleotide sequence of SEQ ID NO: 9.

13. The method of claim 12 , wherein the nucleic acid is conjugated to a ligand, wherein the first RNA strand is a compound of formula (XV):

wherein b is 0 or 1; and

the second RNA strand is a compound of formula (XVI):(XVI);

wherein c and d are independently 0 or 1;

wherein:

Z 1 and Z 2 are the RNA portions of the first and second RNA strands respectively;

Y is O or S;

R 1 is H or methyl;

n is 0, 1, 2 or 3; and

L is the same or different in formulae (XV) and (XVI) and is selected from the group consisting of:

—(CH 2 ) q , wherein q=2-12;

—(CH 2 ) r C(O)—, wherein r=2-12;

—(CH 2 —CH 2 —O) s —CH 2 —C(O)—, wherein s=1-5;

—(CH 2 ) t —CO—NH—(CH 2 ) t — NH—C(O)—, wherein t is independently 1-5;

—(CH 2 ) u —CO—NH—(CH 2 ) u —C(O)—, wherein u is independently 1-5; and

—(CH 2 ) v —NH—C(O)—, wherein v is 2-12; and

wherein the terminal C(O), if present, is attached to the NH group; and

wherein b+c+d is 2 or 3.

14. The method of claim 12 , wherein the first strand comprises the nucleotide a sequence of SEQ ID NO: 9 having modifications as shown below:

SEQ ID

NO:

sequence

modifications

9

5′ AUAACUCUGUCCAUUACCG 3

6162717181736152738

wherein, the specific modifications are depicted by numbers

1=2′F-dU,

2=2′F-dA,

3=2′F-dC,

4=2′F-dG,

5=2′-OMe-rU;

6=2′-OMe-rA;

7=2′-OMe-rC;

8=2′-OMe-rG.

15. The method of claim 1 wherein said first strand is 19-25 nucleotides in length.

16. The method of claim 1 wherein said second strand is 19-25 nucleotides in length.

17. The method of claim 12 wherein said second strand consists of the nucleotide sequence of SEQ ID NO: 10.