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 method of treating ornithine transcarbamylase (OTC) deficiency, comprising administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbyamylase (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,
wherein the mRNA encoding the OTC protein is codon optimized and comprises a polynucleotide sequence at least 90% 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 is encapsulated within a liposome.
2. The method of claim 1 , wherein the mRNA encoding the OTC protein comprises 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.
3. The method of claim 2 , wherein the mRNA encoding the OTC protein comprises SEQ ID NO: 7.
4. The method of claim 1 , wherein the mRNA further comprises the 5′ untranslated region (UTR) sequence of SEQ ID NO: 11.
5. The method of claim 1 , wherein the mRNA further comprises the 3′ untranslated region (UTR) sequence of SEQ ID NO: 12 or SEQ ID NO: 13.
6. The method of claim 1 , 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 method 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 method 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 (,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)) and combinations thereof.
9. The method of claim 6 , wherein the one or more cholesterol-based lipids are at least one of cholesterol, and PEGylated cholesterol.
10. The method of claim 1 , wherein the liposome has a size less than about 100 nm.
11. The method of claim 1 , wherein the mRNA is administered at the effective dose ranging from about 0.01-5.0 mg/kg body weight.
12. The method of claim 1 , wherein the composition is administered intravenously.
13. The method of claim 1 , wherein the composition is administered once a week.
14. The method of claim 1 , wherein the administering of the composition results in an increased OTC protein expression or activity level in serum of the subject as compared to a control level.
15. The method of claim 1 , wherein the administering of the composition results in a reduced urinary orotic acid level in the subject as compared to a control orotic acid level.
16. The method of claim 1 , wherein the administering of the composition results in an increased citrulline level in serum of the subject as compared to a control citrulline level.
17. The method of claim 1 , wherein the mRNA further comprises one or more modified nucleotides.
18. The method of claim 1 , wherein the mRNA is unmodified.