Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency
The present invention provides, among other things, methods of treating ornithine transcarbamylase (OTC) deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase (OTC) protein at an effective dose and an administration interval such that at least one symptom or feature of the OTC deficiency is reduced in intensity, severity, or frequency or has delayed onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.
1. A pharmaceutical composition for treating ornithine transcarbamylase (OTC) deficiency, comprising an mRNA encoding an ornithine transcarbyamylase (OTC) protein and wherein the mRNA encoding the OTC protein comprises a polynucleotide sequence at least 80% identical to SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10, wherein the mRNA encoding the OTC protein is codon optimized, and wherein the OTC protein encoded by the mRNA that is at least 80% identical to SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10 comprises an amino acid sequence at least 98% identical to SEQ ID NO: 5.
2. A pharmaceutical composition for treating ornithine transcarbamylase (OTC) deficiency, comprising an mRNA encoding an ornithine transcarbyamylase (OTC) protein, wherein the mRNA comprises a polynucleotide sequence at least 85% identical to SEQ ID NO: 7, wherein the mRNA encoding the OTC protein is codon optimized, and wherein the OTC protein encoded by the mRNA that is at least 85% identical to SEQ ID NO: 7 comprises an amino acid sequence at least 98% identical to SEQ ID NO: 5.
3. The composition of claim 1 , wherein the mRNA further comprises a 5′ untranslated region (UTR) sequence of SEQ ID NO: 11.
4. The composition of claim 1 , wherein the mRNA further comprises a 3′ untranslated region (UTR) sequence of SEQ ID NO: 12 or SEQ ID NO: 13.
5. The composition of claim 1 , wherein the mRNA is encapsulated within a liposome.
6. The composition of claim 5 , wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.
7. The composition of claim 6 , wherein the one or more cationic lipids comprise a cationic lipid selected from the group consisting of C12-200, MC3, DLinDMA, DLinkC2DMA, cKK-E12, ICE (Imidazole-based), HGT5000, HGT5001, OF-02, DODAC, DDAB, DMRIE, DOSPA, DOGS, DODAP, DODMA and DMDMA, DODAC, DLenDMA, DMRIE, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DLinDAP, DLincarbDAP, DLinCDAP, KLin-K-DMA, DLin-K-XTC2-DMA, HGT4003, and combinations thereof.
8. The composition of claim 6 , wherein the one or more non-cationic lipids are selected from the group consisting of 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)) and combinations thereof.
9. The composition of claim 6 , wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol.
10. The composition of claim 5 , wherein the liposome has a size less than about 100 nm.
11. The composition of claim 1 , wherein the mRNA comprises one or more modified nucleotides.
12. The composition of claim 1 , wherein the mRNA is unmodified.
13. The composition of claim 2 , wherein the mRNA further comprises a 5′ untranslated region (UTR) sequence of SEQ ID NO: 11.
14. The composition of claim 2 , wherein the mRNA further comprises a 3′ untranslated region (UTR) sequence of SEQ ID NO: 12 or SEQ ID NO: 13.
15. The composition of claim 14 , wherein the mRNA is encapsulated within a liposome.
16. The composition of claim 15 , wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.
17. The composition of claim 16 , wherein the one or more cationic lipids comprise a cationic lipid selected from the group consisting of C12-200, MC3, DLinDMA, DLinkC2DMA, cKK-E12, ICE (Imidazole-based), HGT5000, HGT5001, OF-02, DODAC, DDAB, DMRIE, DOSPA, DOGS, DODAP, DODMA and DMDMA, DODAC, DLenDMA, DMRIE, CLinDMA, CpLinDMA, DMOBA, DOcarbDAP, DLinDAP, DLincarbDAP, DLinCDAP, KLin-K-DMA, DLin-K-XTC2-DMA, HGT4003, and combinations thereof.
18. The composition of claim 16 , wherein the one or more non-cationic lipids are selected from the group consisting of 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)) and combinations thereof.
19. The composition of claim 16 , wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol.
20. The composition of claim 15 , wherein the liposome has a size less than about 100 nm.
21. The composition of claim 2 , wherein the mRNA comprises one or more modified nucleotides.
22. The composition of claim 2 , wherein the mRNA is unmodified.
23. The composition of claim 2 , wherein the mRNA comprises a polynucleotide sequence at least 90% identical to SEQ ID NO:7.
24. The composition of claim 2 , wherein the mRNA comprises a polynucleotide sequence at least 95% identical to SEQ ID NO:7.