Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease
AssigneeModernaTX, Inc.
InventorsMichael Albert Zimmer, Xinhua Yan, Mihir Metkar, David Reid
Life of this patent
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Abstract
This disclosure relates to mRNA therapy for the treatment of relaxin-related diseases, disorders or conditions such as, e.g., fibrosis or cardiovascular disease (e.g., acute heart failure or acute coronary syndrome). mRNAs for use in the invention, when administered in vivo, encode relaxin. mRNA therapies of the disclosure increase and/or restore deficient levels of relaxin expression and/or activity in subjects.
Claims94
A lipid nanoparticle comprising a compound of Formula (I):
- or its N-oxide, or a salt or isomer thereof,
- wherein R′a is R′branched;
- wherein
- R′branched is:
- wherein
- denotes a point of attachment;
- wherein Raα, Raβ, Raγ, and Raδ are each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl;
- R2 and R3 are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;
- R4 is selected from the group consisting of —(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and
- wherein
- denotes a point of attachment;
- wherein
- R10 is N(R)2;
- each R is independently selected from the group consisting of C1-6 alkyl, C2-3alkenyl, and H;
- and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
- each R5 is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;
- each R6 is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;
- M and M′ are each independently selected from the group consisting of —C(O)O— and —OC(O)—;
- R′ is a C1-12 alkyl or C2-12 alkenyl;
- l is selected from the group consisting of 1, 2, 3, 4, and 5;
- and
- m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13,
- wherein the lipid nanoparticle comprises a messenger RNA (mRNA) comprising a 5′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:58 and an open reading frame (ORF) encoding a polypeptide comprising a human relaxin protein.
A lipid nanoparticle comprising a compound of Formula (I):
- or its N-oxide, or a salt or isomer thereof,
- wherein R′a is R′branched;
- wherein
- R′branched is:
- wherein
- denotes a point of attachment;
- wherein Raα, Raβ, Raγ, and Raδ are each independently selected from the group consisting of H, C2-12 alkyl, and C2-12 alkenyl;
- R2 and R3 are each independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;
- R4 is selected from the group consisting of —(CH2)nOH, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5, and
- wherein
- denotes a point of attachment;
- wherein
- R10 is N(R)2;
- each R is independently selected from the group consisting of C1-6 alkyl, C2-3alkenyl, and H;
- and n2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
- each R5 is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;
- each R6 is independently selected from the group consisting of C1-3alkyl, C2-3alkenyl, and H;
- M and M′ are each independently selected from the group consisting of —C(O)O— and —OC(O)—;
- R′ is a C1-12 alkyl or C2-12 alkenyl;
- l is selected from the group consisting of 1, 2, 3, 4, and 5;
- and
- m is selected from the group consisting of 5, 6, 7, 8, 9, 10, 11, 12, and 13,
- wherein the lipid nanoparticle comprises a messenger RNA (mRNA) comprising a 3′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:137 and an open reading frame (ORF) encoding a polypeptide comprising a human relaxin protein.
A messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a polypeptide comprising a human relaxin protein, wherein the ORF comprises SEQ ID NO:7.
A messenger RNA (mRNA) comprising a 5′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:58 and an open reading frame (ORF) encoding a polypeptide comprising a human relaxin protein.
A messenger RNA (mRNA) comprising a 3′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:137 and an open reading frame (ORF) encoding a polypeptide comprising a human relaxin protein.
A messenger RNA (mRNA) comprising:
- (i) a 5′-terminal cap;
- (ii) a 5′ untranslated region (UTR) comprising the nucleic acid sequence of SEQ ID NO:58;
- (iii) an open reading frame (ORF) encoding the polypeptide of SEQ ID NO:3, wherein the ORF comprises the nucleotide acid sequence of SEQ ID NO:4;
- (iv) a 3′ UTR comprising the nucleic acid sequence of SEQ ID NO:137;
- and
- (v) a poly-A-region.
A messenger RNA (mRNA) comprising a 3′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:137 and an open reading frame (ORF) encoding a polypeptide.
A messenger RNA (mRNA) comprising a 3′ untranslated region (UTR) comprising the nucleotide sequence of SEQ ID NO:138 and an open reading frame (ORF) encoding a polypeptide.
Dependencies are inferred from the claim text.