CFTR mRNA compositions and related methods and uses
View Patent ↗Pharmaceutical compositions comprising an mRNA-loaded nanoparticle, wherein the mRNA is an in vitro transcribed mRNA and has a coding sequence at least 80% identical to SEQ ID NO: 3, and wherein the mRNA encodes a human cystic fibrosis transmembrane conductance regulator (CFTR) protein comprising the amino acid sequence of SEQ ID NO:1 are provided. The present invention is particularly useful for treating cystic fibrosis.
1. A pharmaceutical composition comprising an mRNA-loaded nanoparticle,
wherein the mRNA is an in vitro transcribed mRNA and has a coding sequence at least 80% identical to SEQ ID NO: 3, and
wherein the mRNA encodes a human cystic fibrosis transmembrane conductance regulator (CFTR) protein comprising the amino acid sequence of SEQ ID NO:1.
2. The pharmaceutical composition of claim 1 , wherein the mRNA has the coding sequence at least 90% identical to SEQ ID NO: 3.
3. The pharmaceutical composition of claim 1 , wherein the mRNA has the coding sequence 100% identical to SEQ ID NO: 3.
4. The pharmaceutical composition of claim 1 , wherein the mRNA comprises a 5′ untranslated region (UTR) and/or a 3′ UTR.
5. The pharmaceutical composition of claim 4 , wherein the 5′-UTR comprises SEQ ID NO: 4 and/or the 3′-UTR comprises SEQ ID NO: 5.
6. The pharmaceutical composition of claim 4 , wherein the mRNA further comprises a poly-A tail.
7. The pharmaceutical composition of claim 6 , wherein the poly-A tail is of at least 70, 100, 120, 150, 200, or 250 residues in length.
8. The pharmaceutical composition of claim 4 , wherein the mRNA further comprises a 5′ cap.
9. The pharmaceutical composition of claim 1 , wherein the mRNA comprises at least one nonstandard nucleobase.
10. The pharmaceutical composition of claim 9 , wherein the nonstandard nucleobase is chosen from one or more of 5-methyl-cytidine, pseudouridine, and 2-thio-uridine.
11. The pharmaceutical composition of claim 1 , wherein the composition is administered to the lung by aerosolization.
12. The pharmaceutical composition of claim 11 wherein the aerosolization is nebulization.
13. The pharmaceutical composition of claim 11 , wherein the administration of the composition results in human CFTR protein expression in epithelial cells of the lung.
14. The pharmaceutical composition of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 1 , wherein the nanoparticle comprises one or more organic cations.
16. The pharmaceutical composition of claim 15 , wherein the one or more organic cations are selected from the group consisting of polyethyleneimine (PEI), protamine, PEGylated protamine, poly-L-lysine (PLL), PEGylated PLL, a cationic lipid and combinations thereof.
17. The pharmaceutical composition of claim 1 , wherein the nanoparticle comprises a polymer.
18. The pharmaceutical composition of claim 17 , wherein the polymer comprises branched PEI with a molecular weight ranging from 10 kDa to 40 kDa.
19. The pharmaceutical composition of claim 1 , wherein the nanoparticle is a liposome.