Compositions and methods for inhibiting transmembrane serine protease 6 (TMPRSS6) expression
Inventors
Blois, Anna Linda • Priest, Christina Marie • PARK, Jihye • Dudek, Henryk
Assignees
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Publication Number
US-12503701-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Oligonucleotides are provided herein that inhibit TMPRSS6 expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with hepcidin deficiency or suppression.
Core Innovation
The invention relates to RNAi oligonucleotides for reducing transmembrane serine protease 6 (TMPRSS6) expression. The oligonucleotide comprises a sense strand and an antisense strand that form a duplex region, and the antisense strand comprises at least 20 contiguous nucleotides of a nucleotide sequence set forth in SEQ ID NO: 600 and a region of complementarity to a TMPRSS6 mRNA target sequence of at least 18 contiguous nucleotides.
The described embodiments include blunt ends and asymmetric duplex configurations with 3′ overhangs and/or 5′ overhangs, unpaired overhang nucleotides, and a sense strand in a stem-loop format. The loop can have a defined size and geometry, including a tetraloop sequence GAAA at positions 27-30 of the sense strand, and S1-Lp-S2 where S1 is complementary to S2 and Lp forms a loop of 3–5 nucleotides between S1 and S2.
The invention further specifies chemical and conjugation features, including 2′-OMe and 2′-F nucleoside modifications, 5′-terminal phosphate and phosphate-mimic/phosphate-analog chemistries, phosphorothioate internucleotide linkages, modified nucleobases, and targeting ligands, especially GalNAc. GalNAc is attached to overhangs or to loop structures, including GalNAc conjugation to nucleotides of the loop Lp using linker moieties.
Claims Coverage
The claims coverage centers on an RNAi oligonucleotide that reduces TMPRSS6 expression by targeting TMPRSS6 mRNA, with independent and dependent claims refining sequence, structural, chemical, and conjugate features. Four inventive features are captured across the claims: antisense complementarity from SEQ ID NO: 600, duplex design, sense strand stem-loop structure, and GalNAc conjugation, with a treatment method for hemochromatosis.
Tmprss6-targeting RNAi duplex with SEQ ID NO: 600 antisense and ≥18-nt complementarity
An RNAi oligonucleotide comprising a sense strand and an antisense strand forming a duplex region, where the antisense strand comprises at least 20 contiguous nucleotides of a nucleotide sequence as set forth in SEQ ID NO: 600 and comprises a region of complementarity to a TMPRSS6 mRNA target sequence of at least 18 contiguous nucleotides, for reducing TMPRSS6 expression.
Position-specific sugar, backbone, and base modifications
The RNAi oligonucleotide includes 2′-OMe and 2′-F modifications, 5′-terminal phosphate and phosphate-mimic/phosphate-analog chemistries, phosphorothioate linkages at defined position pairs, and modified nucleobases.
Sense strand stem-loop tetraloop structure
The RNAi oligonucleotide includes a sense strand in a stem-loop format with a defined loop region, including a tetraloop sequence GAAA at positions 27-30.
GalNAc conjugation at overhangs or loop nucleotide positions
The RNAi oligonucleotide includes GalNAc attached to overhangs or to loop structures, including GalNAc conjugation to nucleotides of the loop Lp using linker moieties.
Treatment of hemochromatosis
A method of treating hemochromatosis by administering a pharmaceutical composition comprising the RNAi oligonucleotide.
Overall, the claims center on TMPRSS6-reducing RNAi oligonucleotides that target TMPRSS6 mRNA using an antisense strand containing at least 20 contiguous nucleotides from SEQ ID NO: 600 and at least 18 contiguous complementary nucleotides, with refinements for duplex structure, sequence modifications, phosphorothioate linkages, stem-loop architecture, GalNAc conjugation, and treatment of hemochromatosis.
Stated Advantages
Increases hepcidin.
Decreases serum iron.
Decreases serum iron saturation.
Reducing transmembrane serine protease 6 (TMPRSS6) expression.
Documented Applications
Reducing transmembrane serine protease 6 (TMPRSS6) expression using an RNAi oligonucleotide.
Treatment of hemochromatosis by administering a pharmaceutical composition comprising the described RNAi oligonucleotide.
Therapeutic use for hepcidin deficiency or suppression-associated diseases including hemochromatosis, hereditary hemochromatosis, beta-thalassemia, and polycythemia vera.
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