Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof
Inventors
BonDurant, Lucas D. • Schlegel, Mark K. • Zuber, Jeffrey • Woods, Lauren Blair • Chickering, Tyler
Assignees
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Publication Number
US-12545914-B2
Publication Date
2026-02-10
Expiration Date
Abstract
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the Angiopoietin-like 3 (ANGPTL3) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an ANGPTL3 gene and to methods of preventing and treating an ANGPTL3-associated disorder, e.g., a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia.
Core Innovation
The invention relates to dsRNA agents for inhibiting expression of an Angiopoietin-like 3 (ANGPTL3) gene in a cell. The dsRNA agent, or salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, and the sense strand comprises at least 19 contiguous nucleotides of the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 while the antisense strand comprises at least 21 contiguous nucleotides of the nucleotide sequence 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661. All nucleotides of the sense strand and all nucleotides of the antisense strand comprise a modification, and at least one modification is a 2′-deoxy-nucleotide modification.
The invention further provides methods of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression by administering a therapeutically effective amount of the dsRNA agent, or salt thereof. The disclosed embodiments include additional chemical modifications such as 2′-O-methyl, 2′-fluoro, phosphorothioate linkages, and 5′-end phosphorus-containing groups, together with a ligand conjugated to the 3′-end of the sense strand. The dsRNA agents are described as designed to reduce ANGPTL3 expression in the subject.
The disclosure also describes carbohydrate ligand conjugates for RNAi/iRNA agents, including N-acetylgalactosamine (GalNAc) and GalNAc-derivative conjugates. Attachment is described using mono-, bi-, or trivalent branched linkers and monovalent, bivalent, or trivalent linker arrangements, including a trivalent branched linker at the 3′ end of the sense strand.
Claims Coverage
The independent claims across the input items focus on modified dsRNA agents that target ANGPTL3 expression. The claimed coverage includes four inventive features: sequence-defined dsRNA for cell inhibition, therapeutic administration for reduction in ANGPTL3 expression, sequence-defined ligand-conjugated modified dsRNA with 2′-OMe/2′-F/2′-deoxy and phosphorothioate features, and GalNAc/L96 conjugation through linker architectures.
Modified dsRNA for inhibiting ANGPTL3 gene expression in a cell
A method of inhibiting expression of an ANGPTL3 gene in a cell by contacting the cell with a dsRNA agent, or salt thereof, where the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region; the sense strand comprises at least 19 contiguous nucleotides of 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46; the antisense strand comprises at least 21 contiguous nucleotides of 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661; all nucleotides of the sense strand and all nucleotides of the antisense strand comprise a modification; and at least one modification is a 2′-deoxy-nucleotide modification.
Therapeutic treatment via modified dsRNA reducing ANGPTL3 expression
A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression by administering to the subject a therapeutically effective amount of a dsRNA agent, or salt thereof, where the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, the strands comprise the specified SEQ ID NO:46 and SEQ ID NO:661 sequences, all nucleotides of both strands comprise a modification, and at least one modification is a 2′-deoxy-nucleotide modification.
Ligand-conjugated modified dsRNA for ANGPTL3-expression reduction
A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression by administering a therapeutically effective amount of a dsRNA agent, or salt thereof, where the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-L96-3′ of SEQ ID NO:20 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19; a, g, c and u are 2′-O-methyl A, G, C, and U, respectively; dA and dG are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro A, C and U, respectively; s is a phosphorothioate linkage; and L96 is a ligand conjugated to the 3′-end of the sense strand.
GalNAc and linker-based dsRNA conjugation
A dsRNA agent comprising sense and antisense strands forming a double stranded region, with a monosaccharide ligand that is N-acetylgalactosamine (GalNAc), GalNAc-derivative conjugates, and attachment using mono-, bi-, or trivalent branched linkers and monovalent, bivalent, or trivalent linker arrangements, including a trivalent branched linker at the 3′ end of the sense strand.
Across the independent claims, the claimed invention centers on modified dsRNA agents that reduce ANGPTL3 expression using defined sense and antisense strands forming a double stranded region, with all nucleotides modified and at least one 2′-deoxy-nucleotide modification in the earlier claims. Additional independent claim coverage includes specified 2′-O-methyl, 2′-fluoro, deoxy, and phosphorothioate features together with a ligand conjugated to the 3′ end of the sense strand, including GalNAc-related conjugates and linker architectures.
Stated Advantages
Inhibiting expression of the ANGPTL3 gene in the cell.
Treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression.
Reduces ANGPTL3 expression in a subject, including decreases in serum lipids and/or decreased ANGPTL3 protein accumulation.
Reducing one or more serum lipids and/or decreasing ANGPTL3 protein accumulation.
Documented Applications
Inhibiting ANGPTL3 gene expression in a cell by contacting the cell with a modified dsRNA agent, or salt thereof.
Treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression by administering a therapeutically effective amount of the modified dsRNA agent, or salt thereof.
Preventing or treating ANGPTL3-associated lipid metabolism disorders, including hyperlipidemia and hypertriglyceridemia, by administering a therapeutically effective amount of the dsRNA agent.
In vitro dsRNA activity assessment in primary cynomolgus hepatocytes and Hep3B cells.
In vivo mouse assessment in an AAV-mediated hANGPTL3 mouse model.
Non-human primate studies assessing ANGPTL3 protein reduction after administration of select lead dsRNAs.
Treatment for ANGPTL3-associated disorders, including lipid metabolism disorders such as hyperlipidemia and hypertriglyceridemia.
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