Synthetic methylmalonyl-CoA mutase transgene for the treatment of MUT class methylmalonic acidemia (MMA)
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsCharles P. Venditti, Randy J. Chandler
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Abstract
Synthetic polynucleotides encoding human methylmalonyl-CoA mutase (synMUT) and exhibiting augmented expression in cell culture and/or in a subject are described herein. An adeno-associated viral (AAV) gene therapy vector encoding synMUT under the control of a liver-specific promoter (AAV2/8-HCR-hAAT-synMUT-RBG) successfully rescued the neonatal lethal phenotype displayed by methylmalonyl-CoA mutase-deficient mice, lowered circulating methylmalonic acid levels in the treated animals, and resulted in prolonged hepatic expression of the product of synMUT transgene in vivo, human methylmalonyl-CoA mutase (MUT).
Claims33
A method of treating a disease or condition mediated by methylmalonyl-CoA mutase, comprising administering to a subject in need thereof, in vivo or by genetic alteration of cells prior to administration, a therapeutic amount of a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) selected from the group consisting of:
- a) a polynucleotide comprising the nucleic acid sequence of SEQ ID NO:1;
- b) a codon optimized polynucleotide comprising a polynucleotide having a nucleic acid sequence with at least about 70% identity to the nucleic acid sequence of SEQ ID NO:1 and encoding a polypeptide according to SEQ ID NO:2, and having equivalent expression in a host to either SEQ ID NO:1 expression or SEQ ID NO:3 expression, wherein the codon optimized polynucleotide having at least about 70% identity to SEQ ID NO:1 does not have the nucleic acid sequence of SEQ ID NO:3.
A method of treating a disease or condition mediated by methylmalonyl-CoA mutase, comprising administering to a subject in need thereof a therapeutic amount of a mature methylmalonyl-CoA mutase produced using a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) selected from the group consisting of:
- (a) a polynucleotide comprising the nucleic acid sequence of SEQ ID NO:1;
- and (b) a codon-optimized polynucleotide comprising a polynucleotide having a nucleic acid sequence with at least about 70% identity to the nucleic acid sequence of SEQ ID NO:
- 1 and encoding a polypeptide comprising residues 33-750 of SEQ ID NO:2, and having equivalent expression in a host to either SEQ ID NO:
- 1 expression or SEQ ID NO:3 expression, wherein the codon-optimized polynucleotide having at least about 70% identity to SEQ ID NO:1 does not have the nucleic acid sequence of SEQ ID NO:3.
A synthetic methylmalonyl-CoA mutase (MUT) polynucleotide (synMUT) comprising a nucleic acid sequence with at least 70% identity to the nucleic acid sequence of SEQ ID NO:1, encoding a polypeptide according to SEQ ID NO:2, and having equivalent expression in a host to either SEQ ID NO:1 expression or SEQ ID NO:3 expression, wherein the synthetic polynucleotide does not have the nucleic acid sequence of SEQ ID NO:3.
Dependencies are inferred from the claim text.