Biodegradable lipids for delivery of nucleic acids
The present invention provides, in part, a biodegradable compound of formula I, and sub-formulas thereof:Formula (I) or a pharmaceutically acceptable salt thereof, where each X independently is O or S, each Y independently is O or S, and each R 1 independently is defined herein; and a liposome composition comprising the cationic lipid of formula I or a sub-formula thereof, and methods of delivering agents, such as nucleic acids including mRNA, in vivo, by administering to a subject the liposome comprising the cationic lipid of formula I or a sub-formula thereof, where the agent is encapsulated within the liposome.
1. A compound according to formula II-a:
or a pharmaceutically acceptable salt thereof,
wherein each n independently is 2 to 6 and each m independently is 3 to 15.
2. A composition for delivery of a polynucleotide comprising a compound of claim 1 .
3. The composition of claim 2 , wherein the composition is a liposome.
4. The composition of claim 3 , wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids, one or more PEG-modified lipids, or a combination thereof.
5. The composition of claim 4 , wherein
the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine) DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)).
6. The composition of claim 4 , wherein the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C 6 -C 20 length.
7. The composition of claim 3 , wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm.
8. A method of delivery of messenger RNA (mRNA) in vivo, comprising
administering to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo;
wherein the liposome comprises a cationic lipid compound of claim 1 .
9. The method of claim 8 , wherein the protein encoded by the mRNA is a cytosolic protein, a secreted protein, or an enzyme.
10. The method of claim 8 , wherein the mRNA comprises one or more modified nucleotides.
11. The method-of claim 10 , wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deaza-guanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.
12. The method-of claim 8 , wherein the mRNA is unmodified.
13. The compound of claim 1 , wherein each n independently is 3 to 5 and each m independently is 5 to 13.
14. The compound of claim 1 , wherein each n independently is 3 or 4 and each m independently is 7 to 11.
15. The compound of claim 1 , wherein each n is the same and is 3 or 4, and each m is the same and is 7 to 11.
16. The method of claim 8 , wherein the protein encoded by the mRNA is expressed in serum.