Compounds and methods for reducing PLN expression
Inventors
KUBLI, Dieter A. • Anderson, Brooke A. • Mullick, Adam • Swayze, Eric E.
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Assignees
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624358-B2
Publication Date
2026-05-12
Expiration Date
Abstract
Provided are oligomeric compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLN RNA in a cell or animal, and in certain instances reducing the amount of phospholamban protein in a cell or animal. Such oligomeric compounds, methods, and pharmaceutical compositions are useful to treat cardiomyopathy, heart failure, or arrhythmia.
Core Innovation
The invention relates to an oligomeric duplex comprising a modified oligonucleotide and a conjugated modified oligonucleotide, each defined by specific chemical notation. The modified oligonucleotide includes adenine, cytosine, guanine, thymine, and uracil nucleobases, together with 2′-MOE, 2′-fluoro, and 2′-OMe sugar moieties, phosphodiester and phosphorothioate internucleoside linkages, and a 5′ vinyl phosphonate group.
The conjugated modified oligonucleotide is defined by a conjugate group [X]1 having a structure identified as SEQ ID NO:1301, or a pharmaceutically acceptable salt thereof. The oligomeric duplex is also described in pharmaceutically acceptable salt forms, including sodium salt and potassium salt embodiments.
The disclosure further describes PLN-targeted oligomeric duplex oligonucleotides and antisense oligomeric duplexes for targeting PLN RNA, with modified oligonucleotide and conjugated modified oligonucleotide portions. It also mentions conjugation to cell-targeting moieties including a transferrin receptor ligand via bicycle peptide BCY17901, as well as conjugate linker chemistry and related duplex embodiments.
Claims Coverage
The independent claims center on structurally defined oligomeric duplexes, with one detailed independent claim combining a modified oligonucleotide and a conjugated modified oligonucleotide, and other independent claims defining oligomeric duplexes by chemical structure. The claim set includes three independent claims and coverage for pharmaceutically acceptable salt forms; dependent claims also mention pharmaceutical compositions with a pharmaceutically acceptable diluent or carrier.
Modified oligonucleotide with defined sugar moieties, internucleoside linkages, and 5′ vinyl phosphonate
An oligomeric duplex comprising a modified oligonucleotide according to SEQ ID NO:1255, with nucleobases A, C, G, T, and U; sugar moieties e (2′-MOE), f (2′-fluoro), and y (2′-OMe); internucleoside linkages o (phosphodiester) and s (phosphorothioate); and a 5′ vinyl phosphonate group (vP).
Conjugated modified oligonucleotide with a defined conjugate group
An oligomeric duplex comprising a conjugated modified oligonucleotide according to SEQ ID NO:1041, with [X]1 as a conjugate group having the structure of SEQ ID NO:1301, or a pharmaceutically acceptable salt thereof.
Oligomeric duplex defined by chemical structure
An oligomeric duplex according to the following chemical structure, or a pharmaceutically acceptable salt thereof.
Oligomeric duplex defined by chemical structure
An oligomeric duplex according to the following chemical structure.
Claim coverage is directed to oligomeric duplexes defined by specified modified oligonucleotide chemistry, including 2′-MOE, 2′-fluoro, 2′-OMe, phosphodiester and phosphorothioate internucleoside linkages, and a 5′ vinyl phosphonate group, together with a conjugated modified oligonucleotide bearing a defined conjugate group structure (SEQ ID NO:1301). Additional independent claims cover duplexes defined by chemical structure, including pharmaceutically acceptable salt forms.
Stated Advantages
Treating cardiomyopathy, heart failure, and arrhythmia by reducing phospholamban (PLN) expression.
Improves activity and/or pharmacokinetic/pharmacodynamic properties versus comparator constructs.
Documented Applications
Reducing phospholamban (PLN) expression for treating cardiomyopathy.
Reducing phospholamban (PLN) expression for treating heart failure.
Reducing phospholamban (PLN) expression for treating arrhythmia.
Therapeutic embodiments for antisense/RNAi treatment targeting PLN nucleic acid (PLN RNA) and PLN protein in heart/cardiovascular injury contexts.
PLN-targeted oligomeric duplex oligonucleotides and antisense oligomeric duplexes for targeting PLN RNA.
Conjugation to cell-targeting moieties including a transferrin receptor ligand via bicycle peptide BCY17901.
Pharmaceutical composition embodiments including the oligomeric duplex together with a pharmaceutically acceptable diluent or carrier.
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