Lipids and compositions for the delivery of therapeutics

1. A lipid having the structure

or a salt or isomer thereof,

wherein:

R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand;

R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol, optionally substituted mPEG, heteroaryl, heterocycle, or linker-ligand;

E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O) 2 N(Q), S(O) 2 , N(Q)S(O) 2 , SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and,

Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl.

2. A lipid particle comprising a lipid of claim 1 .

3. The lipid particle of claim 2 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

4. The lipid particle of claim 2 , wherein the lipid particle consists essentially of

a. a lipid of claim 1 ;

b. a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM;

c. a sterol; and

d. PEG-DMG,

in a molar ratio of about 20-60% lipid of claim 1 : 5-25% neutral lipid:25-55% sterol:0.5-15% PEG-DMG.

5. The lipid particle of claim 2 , further comprising a therapeutic agent.

6. The lipid particle of claim 5 , wherein the therapeutic agent is a nucleic acid.

7. The lipid particle of claim 6 , wherein the nucleic acid is a plasmid.

8. The lipid particle of claim 6 , wherein the nucleic acid is an immunostimulatory oligonucleotide.

9. The lipid particle of claim 6 , wherein the nucleic acid is selected from the group consisting of an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

10. The lipid particle of claim 9 , wherein the nucleic acid is an siRNA.

11. A pharmaceutical composition comprising a lipid particle of claim 5 and a pharmaceutically acceptable excipient, carrier, or diluent.

12. A method of modulating the expression of a target gene in a cell, comprising providing to a cell the lipid particle of claim 5 .

13. The method of claim 12 , wherein the therapeutic agent is selected from an siRNA, an antagomir, an antisense oligonucleotide, and a plasmid capable of expressing an siRNA, a ribozyme, an aptamer or an antisense oligonucleotide.

14. The method of claim 12 , wherein the nucleic acid is mRNA.

15. A method of treating a disease or disorder characterized by overexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 11 , wherein the therapeutic agent is selected from an siRNA, a microRNA, an anti sense oligonucleotide, and a plasmid capable of expressing an siRNA, a microRNA, or an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense RNA comprises a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof.

16. A method of treating a disease or disorder characterized by underexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 11 , wherein the therapeutic agent is mRNA.

17. A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of claim 11 , wherein the therapeutic agent is an immunostimulatory oligonucleotide.

18. The method of claim 17 , wherein the pharmaceutical composition is provided to the patient in combination with a vaccine or antigen.

19. A vaccine comprising the lipid particle of claim 7 and an antigen associated with a disease or pathogen.

20. The vaccine of claim 19 , wherein said antigen is a tumor antigen.

21. The vaccine of claim 19 , wherein said antigen is a viral antigen, a bacterial antigen, or a parasitic antigen.

22. The lipid particle of claim 5 , wherein the molar ratio is 52% lipid:5% neutral lipid:30% sterol:13% PEG-DMG.

23. The method of claim 13 , wherein the target gene is selected from the group consisting of Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, SORT1 gene, XBP1 gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21(WAF1/CIP1) gene, p27(KIP1) gene, PPM1D gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor genes, and p53 tumor suppressor gene.

24. The lipid particle of claim 6 , wherein the nucleic acid is mRNA.