Nucleic acids for inhibiting expression of PROS1 in a cell
Inventors
SCHAEPER, UTE • DAMES, Sibylle • MORRISON, Eliot • PRINCE ELADNANI, Raja • Angelillo-Scherrer, Anne
Assignees
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Publication Number
US-11820971-B2
Publication Date
2023-11-21
Expiration Date
Abstract
The invention relates to nucleic acid products that interfere with or inhibit PROS1 gene expression. It further relates to therapeutic uses of PROS1 inhibition for the treatment of bleeding disorders.
Core Innovation
The invention provides a double-stranded nucleic acid for inhibiting expression of PROS1. The nucleic acid comprises a first strand and a second strand, and the first strand includes a defined nucleotide sequence with 2ʹ-O-Methyl modified RNA nucleotides, 2ʹ deoxy-2ʹ-Fluoro modified RNA nucleotides, and phosphorothioate linkages between adjacent nucleotides.
The claimed embodiments define first- and second-strand structures with modified RNA nucleotides and phosphorothioate linkages, including defined 5ʹ and 3ʹ ends and terminal 5ʹ (E)-vinylphosphonate nucleotide embodiments. The second strand is specified by defined sequences including modified nucleotides such as mG, mC, mU, mA, fU, and fG, and repeating phosphorothioate elements.
The invention further includes conjugates and formulations in which the double-stranded nucleic acid is conjugated to ligands for delivery, including GalNAc-containing ligands for hepatocyte targeting via ASGP-R. Ligand structures are defined using compound formula (II) with saccharide (S), linker groups X1 and X2 attached to a phosphate (P), a branching unit (A), and a bridging unit (X3), with conjugation to X3 via a phosphate or modified phosphate.
Claims Coverage
The consolidated claim set centers on a PROS1-inhibiting double-stranded nucleic acid with defined strand sequences and defined chemical modifications. Dependent claims further refine terminal chemistry, specify second-strand sequence embodiments, add ligand-conjugate embodiments, and include pharmaceutical composition embodiments.
PROS1 inhibiting double-stranded nucleic acid with defined modified first strand
A double-stranded nucleic acid for inhibiting expression of PROS1, comprising a first strand and a second strand, wherein the first strand comprises a defined sequence with m indicating 2ʹ-O-Methyl modified RNA nucleotides, f indicating 2ʹ deoxy-2ʹ-Fluoro modified RNA nucleotides, and (ps) indicating phosphorothioate linkages between adjacent nucleotides.
Terminal 5ʹ (E)-vinylphosphonate first-strand nucleotide
The double-stranded nucleic acid wherein the first strand comprises a terminal 5ʹ (E)-vinylphosphonate nucleotide at its 5ʹ end.
Defined second strand structure with modified repeating elements
The double-stranded nucleic acid wherein the second strand comprises defined 5ʹ and 3ʹ ends and modified nucleotide units including mG, mC, mU, mA, fU, and fG, with repeating phosphorothioate elements.
GalNAc and phosphate-linked ligand conjugates via compound formula (II)
A conjugated double-stranded nucleic acid wherein the nucleic acid is conjugated to a ligand defined by compound formula (II) comprising saccharide (S), linker groups X1 and X2 attached to a phosphate (P), a branching unit (A), and a bridging unit (X3), with conjugation to X3 occurring via a phosphate or modified phosphate.
Pharmaceutical composition including the PROS1 inhibiting double-stranded nucleic acid
A pharmaceutical composition comprising the double-stranded nucleic acid of the claimed invention and pharmaceutically acceptable salts, solvents, delivery vehicles, excipients, carriers, diluents, buffers, preservatives, or a pharmaceutically acceptable salt or solvate of the nucleic acid.
The claim coverage centers on a PROS1-inhibiting double-stranded nucleic acid with defined modified first-strand chemistry, refined second-strand sequence embodiments, optional terminal 5ʹ (E)-vinylphosphonate chemistry, ligand-conjugated forms using compound formula (II), and pharmaceutical composition embodiments.
Stated Advantages
Inhibiting expression of PROS1.
RISC-mediated mRNA degradation of PROS1 mRNA.
Therapeutic use for bleeding disorders, including haemophilia A and haemophilia B.
Prevents acute hemarthrosis in vivo, including reduced knee swelling and intra-articular bleeding outcomes.
Improves haemostatic profiles by restoring thrombin generation when PS activity is reduced in a PS/TFPI context.
Normalizes thrombin generation metrics, including endogenous thrombin potential (ETP), in haemophilia A plasma/PRP after PS inhibition.
Affects thrombus formation in TF-induced venous thromboembolism and FeCl3 arterial injury models.
Improves bleeding outcomes linked to fibrin network changes through effects on the PS/TFPI pathway.
Documented Applications
Therapeutic treatment for bleeding disorders, including haemophilia A and haemophilia B.
In vivo validation in mouse thrombosis and bleeding models, including TF-induced venous thromboembolism and FeCl3 arterial injury.
In haemophilia A and haemophilia B settings, including prevention of acute hemarthrosis outcomes.
Ex vivo evaluation in human haemophilia plasma/PRP to compare PS/TFPI expression correlations for haemophilia-on demand versus prophylaxis and to assess normalization of thrombin generation metrics.
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