Lipid nanoparticle compositions and methods for MRNA delivery
Disclosed herein are compositions and methods for modulating the production of a protein in a target cell. The compositions and methods disclosed herein are capable of ameliorating diseases associated with protein or enzyme deficiencies.
1. A composition comprising an mRNA encoding a cytokine, encapsulated within a lipid nanoparticle,
wherein the lipid nanoparticle has a size less than 150 nm and comprises
(i) a PEG-modified lipid at a molar ratio of greater than 1% of the total lipids in the lipid nanoparticle,
(ii) a cationic lipid at a molar ratio of greater than 10% of the total lipids in the lipid nanoparticle,
(iii) a non-cationic lipid at a molar ratio of greater than 5% of total lipids in the lipid nanoparticle, and
(iv) cholesterol at a molar ratio of greater than 10% of the total lipids in the lipid nanoparticle.
2. The composition of claim 1 , wherein the lipid nanoparticle comprises cationic lipids at a molar ratio of 20% to 70% of the total lipids.
3. The composition of claim 2 , wherein the lipid nanoparticle comprises PEG-modified lipids at a molar ratio of 1% to 15% of the total lipids.
4. The composition of claim 1 , wherein one or more cationic lipids comprise DSPC.
5. The composition of claim 1 , wherein one or more cationic lipids comprise DOPE.
6. The composition of claim 1 , wherein one or more PEG-modified lipids comprise DMG-PEG-2000.
7. The composition of claim 1 , wherein the mRNA comprises a poly A tail of at least 90 nucleotides.
8. The composition of claim 7 , wherein the poly A tail comprises at least 200 nucleotides.
9. The composition of claim 1 , wherein the lipid nanoparticle has a size less than 125 nm.
10. The composition of claim 9 , wherein the lipid nanoparticle has a size less than 100 nm.
11. The composition of claim 1 , wherein the mRNA is modified.
12. The composition of claim 11 , wherein the mRNA comprises pseudouridines.
13. The composition of claim 1 , wherein the mRNA comprises a 5′ UTR.
14. The composition of claim 1 , wherein the mRNA comprises a 3′ UTR.
15. The composition of claim 1 , wherein the mRNA comprises a cap structure.
16. The composition of claim 1 , wherein the cytokine is an IL-12.
17. The composition of claim 1 , wherein the cytokine is an IL-23.
18. A composition comprising an mRNA encoding a cytokine, encapsulated within a lipid nanoparticle, wherein the lipid nanoparticle has a size less than 150 nm and comprises
(i) a PEG-modified lipid at a molar ratio of greater than 1% of the total lipids in the lipid nanoparticle,
(ii) a cationic lipid at a molar ratio of greater than 10% of the total lipids in the lipid nanoparticle,
(iii) a non-cationic lipid at a molar ratio of greater than 5% of total lipids in the lipid nanoparticle, and
(iv) cholesterol at a molar ratio greater than 10% of the total lipids in the lipid nanoparticle, and wherein the mRNA comprises
(i) a 5′-UTR,
(ii) a 3′-UTR,
(iii) a 5′ cap structure, and
(iv) a poly A tail.
19. A composition comprising an mRNA encoding a cytokine, encapsulated within a lipid nanoparticle, wherein the lipid nanoparticle has a size less than 150 nm and comprises
(i) a PEG-modified lipid at a molar ratio of greater than 1% of the total lipids in the lipid nanoparticle,
(ii) a cationic lipid at a molar ratio of greater than 10% of the total lipids in the lipid nanoparticle,
(iii) a non-cationic lipid at a molar ratio of greater than 5% of total lipids in the lipid nanoparticle, and
(iv) cholesterol at a molar ratio greater than 10% of the total lipids in the lipid nanoparticle, and
wherein the mRNA is modified to comprise one or more pseudouridine and the mRNA comprises
(i) a 5′-UTR,
(ii) a 3 ‘-UTR,
(iii) a 5’ cap structure, and
(iv) a poly A tail.