An antisense oligonucleotide (AON) capable of inhibiting ADAR-mediated deamination of a target adenosine present in an editing-site sequence (ESS) of a target RNA molecule, wherein under physiological conditions the ESS would hybridize with an editing-site complementary sequence (ESCS) of an RNA molecule to form a double stranded RNA complex, wherein the AON comprises a sequence configured to compete with the ESCS for hybridization with the ESS.

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).

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount, activity, or expression of the target nucleic acid in a cell. In certain embodiments, hybridization results in selective modulation of the amount, activity, or expression of a target Huntingtin gene or Huntingtin transcript in a cell.

The present invention relates to an oligonucleotide comprising at least one phosphorodithioate internucleoside linkage of formula (I) (I) as defined in the description and in the claim. The oligonucleotide of the invention can be used as a medicement.

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Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of MSH3 RNA in a cell or subject, and in certain instances reducing the amount of MSH3 protein in a cell or subject. These compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a repeat expansion disease. Such symptoms and hallmarks include brain atrophy, muscle atrophy, nerve degeneration, uncontrolled movement, seizure, tremors, muscle weakness, muscle cramping, difficulty swallowing, difficulty speaking, decreased memory, decreased cognition, anxiety, and depression. Non-limiting examples of repeat expansion diseases that benefit from these compounds, methods, and pharmaceutical compositions are myotonic dystrophy (DM1 and DM2), amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, various polyglutamine disorders, Friedrich's ataxia, Fragile X syndrome, or spinocerebellar ataxia (e.g., SCA1, SCA2, SCA3, SCA6, SCAT, SCA8, SCA10, or SCA17).

The present disclosure relates to extracellular vesicles, e.g., exosomes, comprising an antisense oligonucleotide (ASO), wherein the ASO comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within a CEBP/transcript. Also provided herein are methods for producing the exosomes and methods for using the exosomes to treat and/or prevent diseases or disorders.

Disclosed herein are IL-34 inhibitors, including IL-34 antisense oligonucleotide sequences, and methods for treating inflammatory diseases, such as an inflammatory bowel disease, and/or fibrosis, associated with elevated activity or expression of IL-34. Also disclosed are pharmaceutical compositions containing an IL-34 inhibitor, for example, a IL-34 antisense oligonucleotide, useful for treating inflammatory diseases and/or fibrosis and manufacture of medicaments containing a disclosed IL-34 inhibitor to be used in treating inflammatory diseases and/or fibrosis.

Materials and methods for treating a patient with a hemoglobinopathy, both ex vivo and in vivo, and materials and methods for creating permanent changes to the genome that can result in at least one deletion, insertion, modulation, or inactivation of a transcriptional control sequence of a BCL11A gene in a cell by genome editing.

This disclosure relates to oligonucleotides, compositions and methods useful for reducing PCSK9 expression, particularly in hepatocytes. Disclosed oligonucleotides for the reduction of PCSK9 expression may be double-stranded or single-stranded, and may be modified for improved characteristics such as stronger resistance to nucleases and lower immunogenicity. Disclosed oligonucleotides for the reduction of PCSK9 expression may also include targeting ligands to target a particular cell or organ, such as the hepatocytes of the liver, and may be used to treat hypercholesterolemia, atherosclerosis, and/or one or more symptoms or complications thereof.