Polynucleotides encoding very long-chain acyl-coa dehydrogenase for the treatment of very long-chain acyl-coa dehydrogenase deficiency
AssigneeModernaTX, Inc.
InventorsVladimir Presnyak, Paolo Martini
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Abstract
This disclosure relates to mRNA therapy for the treatment of very long-chain specific acyl-CoA dehydrogenase deficiency (VLCADD). mRNAs for use in the invention, when administered in vivo, encode human very long-chain specific acyl-CoA dehydrogenase (VLCAD). mRNA therapies of the disclosure increase and/or restore deficient levels of VLCAD expression and/or activity in subjects. mRNA therapies of the disclosure further decrease abnormal accumulation of acylcarnitine associated with deficient VLCAD activity in subjects.
Claims42
A polynucleotide comprising a messenger RNA (mRNA) comprising:
- (i) a 5′ UTR;
- (ii) an open reading frame (ORF) encoding a human very long-chain specific acyl-CoA dehydrogenase (VLCAD) polypeptide, wherein the ORF has at least 79%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOs:2, 5-11, and 25;
- (iii) a stop codon;
- and
- (iv) a 3′ UTR.
A polynucleotide comprising a messenger RNA (mRNA) comprising:
- (i) a 5′-terminal cap;
- (ii) a 5′ UTR comprising the nucleic acid sequence of SEQ ID NO:3, 27, 38, or 39;
- (iii) an open reading frame (ORF) encoding the very long-chain specific acyl-CoA dehydrogenase (VLCAD) polypeptide of SEQ ID NO:1, wherein the ORF comprises a sequence selected from the group consisting of SEQ ID NOs:2, 5-11, and 25;
- (iv) a 3′ UTR comprising the nucleic acid sequence of SEQ ID NO:4, 29, 30, 111, 150, 175, 176, 177, or 178;
- and
- (vi) a poly-A-region.
The method of any one of claims 31 to 35, wherein 24 hours after the pharmaceutical composition or polynucleotide is administered to the subject the level of an acylcarnitine in the subject is reduced by at least about 100%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% compared to a baseline acylcarnitine level in the subject.
Dependencies are inferred from the claim text.