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.
41 . A method for delivery of messenger RNA (mRNA) for in vivo production of a protein or comprising
administering to a human a composition comprising an mRNA that encodes a protein or a peptide, wherein the mRNA is encapsulated within a lipid nanoparticle and
wherein the administering of the composition results in the expression of the protein or peptide encoded by the mRNA that is detectable in a target tissue at least 48 hours after administration, wherein the lipid nanoparticle comprises one or more ionizable lipids, one or more non-cationic lipids, one or more cholesterols, and one or more PEG-modified lipids.
42 . The method of claim 41 , wherein the one or more ionizable lipids is a ionizable cationic lipid.
43 . The method of claim 41 , wherein one or more non-cationic lipids comprise DSPC or DOPE.
44 . The method of claim 41 , wherein the lipid nanoparticle comprises non-cationic lipids at a molar ratio of 5% to 90% of the total lipids.
45 . The method of claim 41 , wherein the lipid nanoparticle comprises cholesterol.
46 . The method of claim 41 , wherein the lipid nanoparticle comprises PEG-modified lipids at a molar ratio of 0.5% to 20% of the total lipids.
47 . The method of claim 41 , wherein one or more PEG-modified lipids comprise DMG-PEG-2000.
48 . The method of claim 41 , wherein the composition is administered systemically.
49 . The method of claim 41 , wherein the composition is administered intradermally.
50 . The method of claim 41 , wherein the composition is administered intramuscularly.
51 . The method of claim 41 , wherein the composition is administered subcutaneously.
52 . The method of claim 41 , wherein the mRNA is unmodified.
53 . The method of claim 41 , wherein the mRNA is modified.
54 . The method of claim 53 , wherein the mRNA comprises pseudouridines.
55 . The method of claim 41 , wherein the mRNA comprises a 3′ untranslated region, a 5′ untranslated region, a cap structure, and a poly A tail.
56 . The method of claim 41 , wherein the lipid nanoparticle has a size of less than 150 nm.
57 . The method of claim 41 , wherein the administering of the composition confers immunity to a subject.
58 . The method of claim 41 , wherein the target tissue is muscle.
59 . A composition comprising an mRNA encoding a protein or a peptide, encapsulated within a lipid nanoparticle, wherein the lipid nanoparticle has a size less than 150 nm and comprises
(60) a PEG-modified lipid at a molar ratio of greater than 1% of the total lipids in the lipid nanoparticle,
(ii) an ionizable 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.
60 . The composition of claim 59 , wherein the ionizable lipid is a ionizable cationic lipid.
61 . The composition of claim 59 , wherein the lipid nanoparticle comprises cationic lipids at a molar ratio of 20% to 70% of the total lipids.
62 . The composition of claim 59 , wherein the lipid nanoparticle comprises PEG-modified lipids at a molar ratio of 1% to 15% of the total lipids.
63 . The composition of claim 59 , wherein the lipid nanoparticle comprises non-cationic lipids at a molar ratio of 5% to 90% of the total lipids.
64 . The composition of claim 63 , wherein one or more non-cationic lipids comprise DSPC or DOPE.
65 . The composition of claim 62 , wherein one or more PEG-modified lipids comprise DMG-PEG-2000.
66 . The composition of claim 59 , wherein the mRNA comprises a 3′ untranslated region, a 5′ untranslated region, a cap structure, and a poly A tail.
67 . The composition of claim 59 , wherein the lipid nanoparticle has a size less than 125 nm.
68 . The composition of claim 67 , wherein the lipid nanoparticle has a size less than 100 nm.
69 . The method of claim 59 , wherein the mRNA is modified.
70 . The method of claim 69 , wherein the mRNA comprises pseudouridines.