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US-12618069-B2 - Compounds and methods for reducing ATXN3 expression

US12618069B2US 12618069 B2US12618069 B2US 12618069B2US-12618069-B2

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA in a cell or animal, and in certain embodiments reducing the amount of ATXN3 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include motor dysfunction, aggregation formation, and neuron death. Such neurodegenerative diseases include spinocerebellar ataxia type 3 (SCA3).

Inventors

  • Susan M. Freier

Assignees

  • IONIS PHARMACEUTICALS, INC.

Dates

Publication Date
20260505
Application Date
20231012

Claims (20)

  1. 1 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases, wherein the portion is complementary to an equal length portion of nucleobases 34440-34486 of SEQ ID NO: 2.
  2. 2 . The oligomeric compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
  3. 3 . The oligomeric compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
  4. 4 . The oligomeric compound of claim 3 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
  5. 5 . The oligomeric compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
  6. 6 . The oligomeric compound of claim 5 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
  7. 7 . The oligomeric compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
  8. 8 . The oligomeric compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.
  9. 9 . The oligomeric compound of claim 1 , wherein at least one nucleobase of the modified oligonucleotide comprises a modified nucleobase.
  10. 10 . The oligomeric compound of claim 9 , wherein the modified nucleobase is a 5-methylcytosine.
  11. 11 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
  12. 12 . The oligomeric compound of claim 11 , wherein the modified sugar moiety comprises a bicyclic sugar moiety.
  13. 13 . The oligomeric compound of claim 12 , wherein the bicyclic sugar moiety has a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 —; and —O—CH(CH 3 )—.
  14. 14 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety.
  15. 15 . The oligomeric compound of claim 14 , wherein the non-bicyclic sugar moiety comprises a 2′-MOE or 2′-OMe.
  16. 16 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.
  17. 17 . The oligomeric compound of claim 16 , wherein the sugar surrogate is selected from morpholino and PNA.
  18. 18 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide has a sugar motif comprising: a 5′-region consisting of 1-6 linked 5′-nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3′-region consisting of 1-6 linked 5′-nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2′-deoxyribosyl sugar moiety.
  19. 19 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 18-20 linked nucleosides.
  20. 20 . The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides.

Description

SEQUENCE LISTING The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0331SEQ.xml, created on May 19, 2023, which is 2547 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA 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 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 spinocerebellar ataxia type 3(SCA3). BACKGROUND Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is caused by a mutation in the ATXN3 gene and is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. SCA3 is inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the mutation. The diagnosis of SCA3 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in ATXN3. Affected individuals have alleles with 52 to 86 CAG trinucleotide repeats. Such testing detects 100% of affected individuals. Expanded CAG repeats in the ATXN3 gene are translated into expanded polyglutamine repeats (polyQ) in the ataxin-3 protein and this toxic ataxin-3 protein is associated with aggregates. The polyglutamine expanded ataxin-3 protein in these aggregates is ubiquinated and the aggregates contain other proteins, including heat shock proteins and transcription factors. Aggregates are frequently observed in the brain tissue of SCA3 patients. Management of SCA3 is supportive as no medication slows the course of disease; restless legs syndrome and extrapyramidal syndromes resembling parkinsonism may respond to levodopa or dopamine agonists; spasticity, drooling, and sleep problems respond variably to lioresal, atropine-like drugs, and hypnotic agents; botulinum toxin has been used for dystonia and spasticity; daytime fatigue may respond to psychostimulants such as modafinil; accompanying depression should be treated. Riess, O., Rib, U., Pastore, A. et al. Cerebellum (2008) 7: 125. Currently there is a lack of acceptable options for treating neurodegenerative diseases such as SCA3. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases. SUMMARY OF THE INVENTION Provided herein are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA, and in certain embodiments reducing the amount of Ataxin-3 protein in a cell or animal. In certain embodiments, the animal has a neurodegenerative disease. In certain embodiments, the animal has SCA3. In certain embodiments, compounds useful for reducing expression of ATXN3 RNA are oligomeric compounds. In certain embodiments, the oligomeric compound comprises a modified oligonucleotide. Also provided are methods useful for ameliorating at least one symptom or hallmark of a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is SCA3. In certain embodiments symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. In certain embodiments, amelioration of these symptoms results in improved motor function, reduced neuropathy, and reduction in number of aggregates. DETAILED DESCRIPTION OF THE INVENTION It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety. Definitions Unless specific definitions are provided, the nomenclature used in connectio