Novel lipid formulations for nucleic acid delivery

Abstract

The present invention provides novel, stable lipid particles comprising one or more active agents or therapeutic agents, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles. More particularly, the present invention provides stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (such as one or more interfering RNA), methods of making the SNALP, and methods of delivering and/or administering the SNALP.

1 . A nucleic acid-lipid particle comprising:
 (a) a nucleic acid;   (b) a cationic lipid comprising from 50 mol % to 65 mol % of the total lipid present in the particle;   (c) a non-cationic lipid comprising up to 50 mol % of the total lipid present in the particle, wherein the non-cationic lipid comprises a neutral lipid component comprising a phospholipid of from 3 mol % to 15 mol % of the total lipid present in the particle; and   (d) a conjugated lipid that inhibits aggregation of particles.   
     
     
         2 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises an RNA. 
     
     
         3 . The nucleic acid-lipid particle of  claim 2 , wherein the RNA comprises an mRNA. 
     
     
         4 . The nucleic acid-lipid particle of  claim 1 , wherein the phospholipid comprises from 4 mol % to 12 mol % of the total lipid present in the particle. 
     
     
         5 . The nucleic acid-lipid particle of  claim 1 , wherein the phospholipid comprises from 6 mol % to 12 mol % of the total lipid present in the particle. 
     
     
         6 . The nucleic acid-lipid particle of  claim 1 , wherein the neutral lipid component further comprises cholesterol or a derivative thereof. 
     
     
         7 . The nucleic acid-lipid particle of  claim 6 , wherein the cholesterol or derivative thereof comprises from 25 mol % to 45 mol % of the total lipid present in the particle. 
     
     
         8 . The nucleic acid-lipid particle of  claim 6 , wherein the cholesterol or derivative thereof comprises from 40 mol % to 45 mol % of the total lipid present in the particle. 
     
     
         9 . The nucleic acid-lipid particle of  claim 1 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
         10 . The nucleic acid-lipid particle of  claim 9 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
         11 . The nucleic acid-lipid particle of  claim 1 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 0.5 mol % to 2 mol % of the total lipid present in the particle. 
     
     
         12 . The nucleic acid-lipid particle of  claim 1 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 1 mol to 2 mol % of the total lipid present in the particle. 
     
     
         13 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid is fully encapsulated in the nucleic acid-lipid particle. 
     
     
         14 . A pharmaceutical composition comprising a nucleic acid-lipid particle of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         15 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises an interfering RNA. 
     
     
         16 . The nucleic acid-lipid particle of  claim 1 , wherein the phospholipid comprises from 4 mol % to 10 mol % of the total lipid present in the particle. 
     
     
         17 . The nucleic acid-lipid particle of  claim 6 , wherein the cholesterol or derivative thereof comprises from 30 mol % to 40 mol % of the total lipid present in the particle. 
     
     
         18 . The nucleic acid-lipid particle of  claim 6 , wherein the cholesterol or derivative thereof comprises from 30 mol % to 35 mol % of the total lipid present in the particle. 
     
     
         19 . The nucleic acid-lipid particle of  claim 1 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 0.1 mol % to 2 mol % of the total lipid present in the particle. 
     
     
         20 . The nucleic acid-lipid particle of  claim 9 , wherein the PEG has an average molecular weight of about 2,000 daltons. 
     
     
         21 . The nucleic acid-lipid particle of  claim 20 , wherein the PEG comprises a terminal methoxy group. 
     
     
         22 . The nucleic acid-lipid particle of  claim 20 , wherein the PEG is linked to the lipid via an ether moiety. 
     
     
         23 . A method for introducing a nucleic acid into a cell, the method comprising:
 contacting the cell with a nucleic acid-lipid particle of  claim 1 .   
     
     
         24 . A method for the in vivo delivery of a nucleic acid, the method comprising:
 administering to a mammalian subject a nucleic acid-lipid particle of  claim 1 .   
     
     
         25 . A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising:
 administering to the mammalian subject a therapeutically effective amount of a nucleic acid-lipid particle of  claim 1 .   
     
     
         26 . The method of  claim 25 , wherein the disease or disorder is a viral infection. 
     
     
         27 . The method of  claim 25 , wherein the disease or disorder is a liver disease or disorder. 
     
     
         28 . The method of  claim 25 , wherein the disease or disorder is cancer.