LIPID FORMULATION
The invention features a cationic lipid of formula I, an improved lipid formulation comprising a cationic lipid of formula I and corresponding methods of use. Also disclosed are targeting lipids, and specific lipid formulations comprising such targeting lipids.
1 . (canceled)
2 . A lipid formulation comprising a cationic lipid of formula I:
or a pharmaceutically acceptable salt thereof, and a therapeutic agent, wherein the therapeutic agent is a nucleic acid, wherein the nucleic acid is mRNA.
3 . The lipid formulation of claim 2 , comprising 40-65% of the cationic lipid of formula I, 5-10% of a neutral lipid, 25-40% of a sterol, and 0.5-10% of a PEG or PEG-modified lipid.
4 . The lipid formulation of claim 3 , wherein the neutral lipid is selected from DSPC, DPPC, DMPC, POPC, DOPE and SM.
5 . The lipid formulation of claim 3 , wherein the sterol is cholesterol.
6 . The lipid formulation of claim 3 , wherein the PEG lipid is PEG-C 14 to PEG-C 22 , PEG-Cer 14 to PEG-C 20 , or PEG-DSPE.
7 . The lipid formulation of claim 3 , wherein the formulation is prepared by an in-line mixing method.
8 . The lipid formulation of claim 3 , comprising about 57.5% of the cationic lipid of formula I, about 7.5% of the neutral lipid, about 31.5% of the sterol, and about 3.5% of the PEG or PEG-modified lipid.
9 . The lipid formulation of claim 8 , wherein the formulation is prepared by an extrusion method.
10 - 12 . (canceled)
13 . The lipid formulation of claim 3 , wherein the ratio of lipid:nucleic acid is about 3 to about 15.
14 . The lipid formulation of claim 13 , wherein the ratio of lipid:nucleic acid is about 5 to about 13.
15 . The lipid formulation of claim 2 , further comprising at least one apolipoprotein.
16 . The lipid formulation of claim 15 , wherein the apolipotprotein is ApoE, active polymorphic forms, isoforms, variants and mutants, and fragments or truncated forms thereof.
17 . The lipid formulation of claim 2 , further comprising a targeting lipid.
18 . The formulation of claim 17 , wherein the targeting lipid comprises N-acetyl galactosamine.
19 . The formulation of claim 18 , wherein the N-acetyl galactosamide comprises at least a mono-, bi- or a triantennary sugar unit.
20 . The formulation of claim 17 , wherein said targeting lipid is present in the formulation in a molar amount of from about 0.001% to about 5%.
21 . The formulation of claim 17 , wherein said targeting lipid is the compound selected from the group consisting of Formula II, Formula III, Formula VI and Formula VII:
22 . The lipid formulation of claim 3 , comprising about 50% of cationic lipid of formula I, about 10% of the neutral lipid, about 38.5% of the sterol, and about 1.5% of the PEG or PEG-modified lipid.
23 . The lipid formulation of claim 3 , comprising about 50% of cationic lipid of formula I, about 10% of the neutral lipid, about 35% of the sterol, and about 5% of the PEG or PEG-modified lipid.
24 . The lipid formulation of claim 3 , comprising about 57.2% of cationic lipid of formula I, about 7.1% of the neutral lipid, about 34.3% of the sterol, and about 1.4% of the PEG or PEG-modified lipid.
25 . A method of delivering a therapeutic agent to a cell comprising administering to a subject the lipid formulation of claim 2 .
26 - 29 . (canceled)
30 . A method of modulationg the expression of a target gene in a cell, the method comprising providing to a cell the lipid formulation of claim 3 .