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 - 46 . (canceled) 
     
     
         47 . A lipid particle comprising:
 (a) an mRNA;   (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 a mixture of a phospholipid and a sterol, wherein the phospholipid comprises from 3 mol % to 15 mol % of the total lipid present in the particle and the sterol comprises from 30 mol % to 45 mol % of the total lipid present in the particle; and   (d) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle.   
     
     
         48 . The lipid particle of  claim 47 , wherein the cationic lipid comprises from 50 mol % to 60 mol % of the total lipid present in the particle. 
     
     
         49 . The lipid particle of  claim 47 , wherein the phospholipid comprises dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), or a mixture thereof. 
     
     
         50 . The lipid particle of  claim 47 , wherein the phospholipid comprises from 4 mol % to 12 mol % of the total lipid present in the particle. 
     
     
         51 . The lipid particle of  claim 47 , wherein the sterol comprises cholesterol or a derivative thereof. 
     
     
         52 . The lipid particle of  claim 47 , wherein the sterol comprises from 30 mol % to 40 mol % of the total lipid present in the particle. 
     
     
         53 . The lipid particle of  claim 47 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
         54 . The lipid particle of  claim 53 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
         55 . The lipid particle of  claim 54 , wherein the PEG-DAA conjugate comprises a PEG-dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-distearyloxypropyl (PEG-DSA) conjugate, or a mixture thereof. 
     
     
         56 . The lipid particle of  claim 47 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 1 mol % to 2 mol % of the total lipid present in the particle. 
     
     
         57 . The lipid particle of  claim 47 , wherein the mRNA is fully encapsulated in the lipid particle. 
     
     
         58 . A pharmaceutical composition comprising a lipid particle of  claim 47  and a pharmaceutically acceptable carrier. 
     
     
         59 . A method for introducing an mRNA into a cell, the method comprising:
 contacting the cell with a lipid particle of  claim 47 .   
     
     
         60 . A method for the in vivo delivery of an mRNA, the method comprising:
 administering to a mammalian subject a lipid particle of  claim 47 .   
     
     
         61 . 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 lipid particle of  claim 47 .   
     
     
         62 . The method of  claim 61 , wherein the disease or disorder is a viral infection. 
     
     
         63 . The method of  claim 61 , wherein the disease or disorder is a liver disease or disorder. 
     
     
         64 . The method of  claim 61 , wherein the disease or disorder is cancer.