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US 2022/0243182 A1Published application
Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease
AssigneeModernaTX, Inc.
InventorsPaolo G. V. Martini, Vladimir Presnyak, Paloma Hoban Giangrande, Kimberly Ann Coughlan
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Abstract
This disclosure relates to mRNA therapy for the treatment of maple syrup urine disease (MSUD). mRNAs for use in the invention, when administered in vivo, encode branched chain α-ketoacid dehydrogenase complex (BCKDC) E1α, E1β, or E2mRNA therapies of the disclosure increase and/or restore deficient levels of E1α, E1β, or E2 expression and/or BCKDC activity in subjects. mRNA therapies of the invention further decrease abnormal accumulation of branched chain amino acids associated with deficient BCKDC activity in subjects.
Claims105
A pharmaceutical composition comprising an mRNA, said mRNA comprising an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1α polypeptide, wherein the composition when administered as a single intravenous dose to a human subject in need thereof is sufficient to:
- (i) increase the level of BCKDC activity in liver tissue to within at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal BCKDC activity level for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (ii) increase the level of BCKDC activity in liver tissue at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold compared to the human subject's baseline BCKDC activity level or a reference BCKDC activity level in a human subject having maple syrup urine disease (MSUD) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iii) reduce liver levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline liver leucine, isoleucine, and/or valine levels, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iv) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (v) reduce liver levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold as compared to the human subject's baseline liver leucine, isoleucine, and/or valine level, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (vi) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold at least 5-fold, at least 10-fold, at least 20-fold or at least 50-fold as compared to the human subject's baseline plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- and/or
- (vii) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine to less than 1,110, less than 1,100, less than 1,000, less than 950, less than 900, less than 850, less than 800, less than 750, less than 700, less than 650, less than 600, less than 550, less than 500, less than 450, less than 400, less than 350, less than 300, less than 250, less than 200, less than 150, less than 100, or less than 95 μM in a patient with MSUD for at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration.
5 more elements
A pharmaceutical composition comprising an mRNA, said mRNA comprising an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1β polypeptide, wherein the composition when administered as a single intravenous dose to a human subject in need thereof is sufficient to:
- (i) increase the level of BCKDC activity in liver tissue to within at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal BCKDC activity level for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (ii) increase the level of BCKDC activity in liver tissue at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold compared to the human subject's baseline BCKDC activity level or a reference BCKDC activity level in a human subject having maple syrup urine disease (MSUD) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iii) reduce liver levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline liver leucine, isoleucine, and/or valine levels, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iv) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (v) reduce liver levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold as compared to the human subject's baseline liver leucine, isoleucine, and/or valine level, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (vi) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold at least 5-fold, at least 10-fold, at least 20-fold or at least 50-fold as compared to the human subject's baseline plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- and/or
- (vii) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine to less than 1,110, less than 1,100, less than 1,000, less than 950, less than 900, less than 850, less than 800, less than 750, less than 700, less than 650, less than 600, less than 550, less than 500, less than 450, less than 400, less than 350, less than 300, less than 250, less than 200, less than 150, less than 100, or less than 95 μM in a patient with MSUD for at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration.
5 more elements
A pharmaceutical composition comprising an mRNA, said mRNA comprising an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E2 polypeptide, wherein the composition when administered as a single intravenous dose to a human subject in need thereof is sufficient to:
- (i) increase the level of BCKDC activity in liver tissue to within at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal BCKDC activity level for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (ii) increase the level of BCKDC activity in liver tissue at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold compared to the human subject's baseline BCKDC activity level or a reference BCKDC activity level in a human subject having maple syrup urine disease (MSUD) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iii) reduce liver levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline liver leucine, isoleucine, and/or valine levels, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iv) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (v) reduce liver levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold as compared to the human subject's baseline liver leucine, isoleucine, and/or valine level, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (vi) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold at least 5-fold, at least 10-fold, at least 20-fold or at least 50-fold as compared to the human subject's baseline plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- and/or
- (vii) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine to less than 1,110, less than 1,100, less than 1,000, less than 950, less than 900, less than 850, less than 800, less than 750, less than 700, less than 650, less than 600, less than 550, less than 500, less than 450, less than 400, less than 350, less than 300, less than 250, less than 200, less than 150, less than 100, or less than 95 μM in a patient with MSUD for at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration.
5 more elements
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises a microRNA (miR) binding site.
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises a 3′ UTR, said 3′ UTR comprising a nucleic acid sequence at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a 3′ UTR sequence of SEQ ID NO:4, 49, 50, 111, 150, 176, 177, or 178.
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises a 5′ UTR, said 5′ UTR comprising a nucleic acid sequence at least 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a 5′ UTR sequence of SEQ ID NO:3, 45, 47, or 48.
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises a 5′ terminal cap.
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises a poly-A region.
The pharmaceutical composition of any one of the preceding claims, wherein the mRNA comprises at least one chemically modified nucleobase, sugar, backbone, or any combination thereof.
A pharmaceutical composition comprising a first mRNA, a second mRNA, and a third mRNA, wherein the first mRNA comprises a first open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1α polypeptide, wherein the second mRNA comprises a second ORF encoding a BCKDC E1β polypeptide, wherein the third mRNA comprises a third ORF encoding a BCKDC E2 polypeptide, and wherein the composition when administered intravenously once every 7-10 days to a human subject in need thereof is sufficient to:
- (i) increase the level of BCKDC activity in liver tissue to within at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal BCKDC activity level for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (ii) increase the level of BCKDC activity in liver tissue at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold compared to the human subject's baseline BCKDC activity level or a reference BCKDC activity level in a human subject having maple syrup urine disease (MSUD) for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iii) reduce liver levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline liver leucine, isoleucine, and/or valine levels, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (iv) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to the human subject's baseline plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, or urine leucine, isoleucine, and/or valine level, respectively, in a human subject having MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (v) reduce liver levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, or at least 50-fold as compared to the human subject's baseline liver leucine, isoleucine, and/or valine level, respectively, or a reference liver leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- (vi) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine at least 1.5-fold, at least 2-fold at least 5-fold, at least 10-fold, at least 20-fold or at least 50-fold as compared to the human subject's baseline plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, or a reference plasma, serum, and/or urine leucine, isoleucine, and/or valine level, respectively, in a patient with MSUD for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration;
- and/or
- (vii) reduce plasma, serum, and/or urine levels of leucine, isoleucine, and/or valine to less than 1,110, less than 1,100, less than 1,000, less than 950, less than 900, less than 850, less than 800, less than 750, less than 700, less than 650, less than 600, less than 550, less than 500, less than 450, less than 400, less than 350, less than 300, less than 250, less than 200, less than 150, less than 100, or less than 95 μM in a patient with MSUD for at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or at least 120 hours post-administration.
5 more elements
A pharmaceutical composition comprising a first mRNA, a second mRNA, and a third mRNA, wherein:
- the first mRNA comprises a first open reading frame (ORF) encoding a human branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1α polypeptide, wherein the first 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, 5-8, 20-23, 51-59, and 211;
- the second mRNA comprises a second ORF encoding a human BCKDC E1β polypeptide, wherein the second 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:10-13, 60-63, and 212;
- and
- the third mRNA comprises a third ORF encoding a human BCKDC E2 polypeptide, wherein the third 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:15-18 and 64-67.
1 more element
The pharmaceutical composition of 33, wherein:
- the E1α polypeptide comprises the amino acid sequence set forth in SEQ ID NO:1 or 19;
- the E1β polypeptide comprises the amino acid sequence set forth in SEQ ID NO:9;
- and
- the E2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO:14.
1 more element
A polynucleotide comprising an mRNA comprising:
- (i) a 5′ UTR;
- (ii) an open reading frame (ORF) encoding a human branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1α 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, 5-8, 20-23, 51-59, and 211;
- (iii) a stop codon;
- and
- (iv) a 3′ UTR.
2 more elements
A polynucleotide comprising an mRNA comprising:
- (i) a 5′ UTR;
- (ii) an open reading frame (ORF) encoding a human branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1β 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:10-13, 60-63, and 212;
- (iii) a stop codon;
- and
- (iv) a 3′ UTR.
2 more elements
A polynucleotide comprising an mRNA comprising:
- (i) a 5′ UTR;
- (ii) an open reading frame (ORF) encoding a human branched-chain α-ketoacid dehydrogenase complex (BCKDC) E2 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:15-18 and 64-67;
- (iii) a stop codon;
- and
- (iv) a 3′ UTR.
2 more elements
A polynucleotide comprising an mRNA comprising:
- (i) a 5′-terminal cap;
- (ii) a 5′ UTR comprising the nucleic acid sequence of SEQ ID NO:3, 45, 47, or 48;
- (iii) an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1α polypeptide, wherein the ORF comprises a sequence selected from the group consisting of SEQ ID NOs:2, 5-8, 20-23, 51-59, and 211;
- (iv) a 3′ UTR comprising the nucleic acid sequence of SEQ ID NO:4, 49, 50, 111, 150, 176, 177, or 178;
- and
- (vi) a poly-A-region.
3 more elements
A polynucleotide comprising an mRNA comprising:
- (i) a 5′-terminal cap;
- (ii) a 5′ UTR comprising the nucleic acid sequence of SEQ ID NO:3, 45, 47, or 48;
- (iii) an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E1β polypeptide, wherein the ORF comprises a sequence selected from the group consisting of SEQ ID NOs:10-13, 60-63, and 212;
- (iv) a 3′ UTR comprising the nucleic acid sequence of SEQ ID NO:4, 49, 50, 111, 150, 176, 177, or 178;
- and
- (vi) a poly-A-region.
3 more elements
A polynucleotide comprising an mRNA comprising:
- (i) a 5′-terminal cap;
- (ii) a 5′ UTR comprising the nucleic acid sequence of SEQ ID NO:3, 45, 47, or 48;
- (iii) an open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) E2 polypeptide, wherein the ORF comprises a sequence selected from the group consisting of SEQ ID NOs:15-18 and 64-67;
- (iv) a 3′ UTR comprising the nucleic acid sequence of SEQ ID NO:4, 49, 50, 111, 150, 176, 177, or 178;
- and
- (vi) a poly-A-region.
3 more elements
Dependencies are inferred from the claim text.