Lipid formulated dsRNA targeting the PCSK9 gene

1. A composition comprising a nucleic acid lipid particle comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human PCSK9 gene in a cell, wherein:

the nucleic acid lipid particle comprises a lipid formulation comprising 45-65 mol % of a cationic lipid, 5 mol % to about 10 mol %, of a non-cationic lipid, 25-40 mol % of a sterol, and 0.5-5 mol % of a PEG or PEG-modified lipid and the cationic lipid comprises MC3 (((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate),

the dsRNA consists of a sense strand and an antisense strand,

wherein the sense strand consists of the nucleotide sequence of SEQ ID NO:1227 and the antisense strand consists of the nucleotide sequence of SEQ ID NO:1228.

2. The composition of claim 1 , wherein each strand is modified as follows to include a 2′-O-methyl ribonucleotide as indicated by a lower case letter “c” or “u” and a phosphorothioate as indicated by a lower case letter “s”:

the dsRNA consists of a sense strand consisting of

SEQ ID NO:1229 (5′-uucuAGAccuGuuuuGcuuTsT-3′)

and an antisense strand consisting of

SEQ ID NO:1230 (5′-AAGcAAAAcAGGUCuAGAATsT-3′).

3. The composition of claim 1 or 2 , wherein the lipid formulation is selected from the group consisting of:

LNP11

MC3/DSPC/Cholesterol/PEG-DMG

50/10/38.5/1.5

LNP14

MC3/DSPC/Cholesterol/PEG-DMG

40/15/40/5

LNP15

MC3/DSPC/Cholesterol/PEG-DSG/GalNAc-PEG-DSG

50/10/35/4.5/0.5

LNP16

MC3/DSPC/Cholesterol/PEG- DMG

50/10/38.5/1.5

LNP17

MC3/DSPC/Cholesterol/PEG-DSG

50/10/38.5/1.5

LNP18

MC3/DSPC/Cholesterol/PEG-DMG

50/10/38.5/1.5

LNP19

MC3/DSPC/Cholesterol/PEG-DMG

50/10/35/5

LNP20

MC3/DSPC/Cholesterol/PEG-DPG

50/10/38.5/1.5.

4. The composition of claim 1 or claim 2 , further comprising a lipoprotein.

5. The composition of claim 1 or claim 2 , further comprising apolipoprotein E (ApoE).

6. The composition of claim 5 , wherein the dsRNA is conjugated to a lipophile.

7. The composition of claim 6 , wherein the lipophile is cholesterol.

8. The composition of claim 5 , wherein the ApoE is reconstituted with at least one amphiphilic agent.

9. The composition of claim 8 , wherein the amphiphilic agent is a phospholipid.

10. The composition of claim 8 , wherein the amphilic agent is a phospholipid selected from the group consisting of dimyristoyl phosphatidyl choline (DMPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), egg phosphatidylcholine (EPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), -phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), and combinations thereof.

11. The composition of claim 9 , wherein the ApoE is reconstituted high density lipoprotein (rHDL).

12. The composition of claim 3 , further comprising a lipoprotein.

13. The composition of claim 3 , further comprising apolipoprotein E (ApoE).

14. The composition of claim 13 , wherein the dsRNA is conjugated to a lipophile.

15. The composition of claim 14 , wherein the lipophile is cholesterol.

16. The composition of claim 15 , wherein the ApoE is reconstituted with at least one amphiphilic agent.

17. The composition of claim 16 , wherein the amphiphilic agent is a phospholipid.

18. The composition of claim 16 , wherein the amphilic agent is a phospholipid selected from the group consisting of dimyristoyl phosphatidyl choline (DMPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), egg phosphatidylcholine (EPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), -phosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), and combinations thereof.

19. The composition of claim 13 , wherein the ApoE is reconstituted high density lipoprotein (rHDL).

20. The composition of claim 3 , wherein the lipid formulation is LNP11.

21. The composition of claim 3 , wherein the lipid formulation is LNP14.

22. The composition of claim 3 , wherein the lipid formulation is LNP15.

23. The composition of claim 3 , wherein the lipid formulation is LNP16.

24. The composition of claim 3 , wherein the lipid formulation is LNP17.

25. The composition of claim 3 , wherein the lipid formulation is LNP18.

26. The composition of claim 3 , wherein the lipid formulation is LNP19.

27. The composition of claim 3 , wherein the lipid formulation is LNP20.