Compounds and methods for reducing ATXN3 expression
Inventors
Freier, Susan M. • Kordasiewicz, Holly
Assignees
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Publication Number
US-12350285-B2
Publication Date
2025-07-08
Expiration Date
Abstract
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 mRNA in a cell or animal, and in certain instances reducing the amount of Ataxin-3 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to prevent or ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include SCA3.
Core Innovation
The disclosure relates to antisense compounds and antisense/oligonucleotide-based therapeutics directed to ATXN3 mRNA and, in some instances, Ataxin-3 protein. The approach uses oligomeric compounds and oligomeric duplexes that act through antisense mechanisms such as RNase H cleavage via an RNA:DNA duplex and RNA interference mediated by Argonaute and RISC, and may also involve splicing alteration and translation inhibition.
The core chemical concept is an oligomeric compound comprising a modified oligonucleotide with defined nucleobase sequence constraints and a regional sugar motif architecture. The 5′-region and the 3′-region nucleosides include a modified sugar moiety, while the central region nucleosides include an unmodified DNA sugar moiety; the disclosure further encompasses modified oligonucleotides with modified sugar moieties and modified internucleoside linkages.
The disclosure targets ATXN3 as a disease-associated molecular target and identifies hotspot regions within SEQ ID NO: 1, including nucleobase positions 614-637, 833-852, and 1091-1131. It describes modified oligonucleotides designed as gapmers, including 5-8-5 MOE gapmers with mixed phosphodiester/phosphorothioate internucleoside linkages, and provides examples showing reduction of human ATXN3 mRNA in vitro.
Claims Coverage
The independent claims cover four inventive features centered on modified oligonucleotides, sequence complementarity, and duplex formation.
Regional sugar motif with modified 5′ and 3′ sugars and unmodified central DNA sugar
An oligomeric compound or modified oligonucleotide consisting of 12-20 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of SEQ ID NO: 73-75, with a sugar motif comprising a 5′-region of 1-5 linked 5′-nucleosides, a central region of 6-10 linked central region nucleosides, and a 3′-region of 1-5 linked 3′-region nucleosides, where the 5′- and 3′-region nucleosides comprise a modified sugar moiety and the central region nucleosides comprise an unmodified DNA sugar moiety.
Full complementarity to a portion of nucleobases 614-637 of SEQ ID NO: 1 with at least 90% complementarity across the modified oligonucleotide
An oligomeric compound comprising a modified oligonucleotide consisting of 8-20 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 614-637 of SEQ ID NO: 1, wherein the nucleobase sequence is at least 90% complementary to SEQ ID NO: 1 over the entirety of the modified oligonucleotide, with the same regional sugar motif of modified 5′- and 3′-region nucleosides and unmodified central DNA sugar nucleosides.
Oligomeric duplex with at least 90% complementary region between first and second oligomeric compounds
An oligomeric duplex comprising a first oligomeric compound with a modified oligonucleotide of 12-30 linked nucleosides having at least 12 contiguous nucleobases of SEQ ID NO: 73-75 and at least one modification selected from a modified sugar moiety and a modified internucleoside linkage, and a second oligomeric compound having a region at least 90% complementary to the first oligomeric compound.
Across the independent claims, the inventive coverage centers on modified oligonucleotides with contiguous nucleobase selections from SEQ ID NO: 73-75 or defined complementarity to SEQ ID NO: 1, including a 100% complementary portion to nucleobases 614-637 and at least 90% overall complementarity. These constructs are combined with a specified regional sugar motif in which the 5′- and 3′-regions include modified sugar moieties and the central region includes unmodified DNA sugars, and the duplex claim further requires at least 90% complementarity between two oligomeric compounds.
Stated Advantages
Reduced ATXN3 mRNA in vitro.
Potential impact on disease-associated molecular targets associated with SCA3, including ataxia, neuropathy, and aggregate formation.
Selectivity is addressed by reduced hybridization to non-target nucleic acids.
Documented Applications
Treatment of neurodegenerative disease hallmarks associated with SCA3.
Use against ATXN3 mRNA and, in some instances, Ataxin-3 protein.
Evaluation with in vitro and in vivo data.
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