Oligomeric compound for inhibiting expression of factor XI
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Publication Number
US-12378552-B2
Publication Date
2025-08-05
Expiration Date
Abstract
Products, compositions, and their uses are provided. In particular, nucleic acid products that modulate, in particular interfere with or inhibit, Factor XI (FXI) gene expression are provided. The products can be oligomeric compounds that comprise at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250.
Core Innovation
The claimed invention is an oligomeric compound that inhibits Factor XI (FXI) expression through RNA interference and comprises a single oligonucleotide strand. The single strand consists of a modified or unmodified oligonucleotide selected from specified sequence identifiers. The disclosure describes modified oligonucleotides, self-dimerizing duplex or hairpin constructs, terminal stabilizers, 5′-vinyl-phosphonate, 2′-fluoro modifications, backbone modifications, and ligand conjugation including N-acetyl-galactosamine moieties.
Pharmaceutical compositions comprise the oligomeric compound and a physiologically acceptable excipient for the treatment of thromboembolic disorders. Reported evaluations include screening results, concentration-dependent reductions of FXI expression in primary human hepatocytes, long-lasting FXI downregulation and activity knockdown in vivo, and increased activated partial thromboplastin time with prothrombin time broadly unchanged [procedural detail omitted for safety]. Because the background section is omitted, the problem being solved is not explicitly described in patent.
Claims Coverage
The provided claims identify one independent claim and five dependent claim limitations, representing six inventive features directed to the single-strand FXI-inhibiting compound and associated structural, compositional, and therapeutic refinements.
Single-strand FXI-inhibiting oligomeric compound
The independent claim covers an oligomeric compound that inhibits expression of Factor XI (FXI) and comprises a single oligonucleotide strand.
Specified oligonucleotide sequences
The single strand consists of a modified or unmodified oligonucleotide selected from specified sequence identifiers, with dependent claims reciting a narrowed sequence subset.
N-acetyl-galactosamine ligand
A dependent claim specifies that the compound comprises one or more ligands comprising one or more N-acetyl-galactosamine moieties.
Inverted terminal-end nucleoside
A dependent claim specifies an inverted terminal-end nucleoside attached to an adjacent nucleoside through either their respective 3′ carbons or their respective 5′ carbons.
Composition with an excipient
A dependent claim covers a composition comprising the oligomeric compound and a physiologically acceptable excipient.
Treatment of specified thrombotic disorders
A dependent claim covers treating an individual in need thereof for deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease, or end-stage renal disease (ESRD) by administering the oligomeric compound.
The claim coverage centers on a single-strand oligomeric compound selected from specified sequence identifiers for inhibiting FXI expression, along with dependent claims defining sequence subsets, ligand conjugates, inverted terminal nucleosides, pharmaceutical excipients, and specific thrombotic indications.
Stated Advantages
The claimed oligomeric compound inhibits FXI expression.
The described GalNAc-conjugated construct shows efficient, long-lasting FXI activity knockdown.
The reported APTT and PT results support FXI specificity.
No liver-enzyme elevation or hematology changes are reported in the described evaluation.
Documented Applications
Administration of the oligomeric compound to an individual in need of treatment for deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease, or end-stage renal disease (ESRD).
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