MRNA THERAPY FOR UREA CYCLE DISORDERS
Disclosed herein are compositions and methods of modulating the expression of gene or the production of a protein by transfecting target cells with nucleic acids. The compositions disclosed herein demonstrate a high transfection efficacy and are capable of ameliorating diseases associated with protein or enzyme deficiencies.
1 - 30 . (canceled)
31 . A method of treating a urea cycle disorder comprising
administering to a subject suffering from or susceptible to a urea cycle disorder, a composition comprising an mRNA encoding an enzyme, encapsulated within a liposome;
wherein the enzyme is selected from ornithine transcarbamylase (OTC), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase 1 (ASS1) argininosuccinate lyase (ASL), or arginase (ARG).
32 . The method of claim 31 , wherein the enzyme is ASS1.
33 . The method of claim 31 , wherein the liposome comprises one or more cationic lipids, one or more or non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids and has a size less than about 100 nm.
34 . The method of claim 31 , wherein the liposome has a size less than about 75 nm.
35 . The method of claim 33 , wherein the one or more cationic lipids carry a net positive charge at physiological pH.
36 . The method of claim 33 , wherein the one or more cationic lipids constitute about 20-70% of the total lipids present in the liposome.
37 . The method of claim 33 , wherein the one or more non-cationic lipids comprise DOPE.
38 . The method of claim 33 , wherein the one or more PEG-modified lipids comprise DMG-PEG-2000 or C8-PEG-2000.
39 . The method of claim 33 , wherein the one or more PEG-modified lipids comprise a polyethylene glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C 20 length.
40 . The method of claim 33 , wherein the one or more PEG-modified lipids constitute up to about 20% by molar of the total lipids present in the liposome.
41 . The method of claim 31 , wherein the composition is administered intravenously.
42 . The method of claim 31 , wherein the composition is administered bi-weekly.
43 . The method of claim 31 , wherein the composition is administered monthly.
44 . The method of claim 31 , wherein the mRNA is administered systemically.
45 . The method of claim 31 , wherein the administering of the composition results in increased expression of the enzyme encoded by the mRNA in the liver.
46 . The method of claim 31 , wherein the mRNA is modified to enhance stability.
47 . The method of claim 46 , wherein the mRNA is modified to include a modified nucleotide, an alteration to the 5′ or 3′ untranslated region, a cap structure or a poly A tail.
48 . The method of claim 47 , wherein the mRNA is modified to include a pseudouridine.