Among other things, the present disclosure provides oligonucleotides, compositions, and methods thereof. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., knockdown ability, stability, delivery, etc. In some embodiments, the oligonucleotides decrease the expression, activity and/or level of a C9orf72 gene, including but not limited to, one comprising a repeat expansion, or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in treatment of C9orf72-related disorders.

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 PLP1 RNA in a cell or subject, and in certain instances reducing the amount of proteolipid protein 1 in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a leukodystrophy. Such symptoms and hallmarks include hypotonia, nystagmus, optic atrophy, respiratory distress, motor delays, cognitive dysfunction, speech dysfunction, spasticity, ataxia, seizures, choreiform movements, and death. Such leukodystrophies include Pelizaeus-Merzbacher disease.

Provided herein are methods of treating cancer or an autoimmune disease comprising administering a liposome that comprises neutral phospholipids and a P-ethoxy oligonucleotide that targets a IGF-1R-encoding polynucleotide.

Provided herein are improved delivery systems for oligonucleotides, said delivery system comprising a liposome that comprises neutral phospholipids and a P-ethoxy oligonucleotide, which targets a STAT3-encoding polynucleotide. Methods of treating patients with said delivery systems are also provided.

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.

This disclosure relates to novel MAPT targeting sequences. Novel MAPT targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.

This disclosure relates to novel SNCA targeting sequences. Novel SNCA targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of FXI RNA in a cell or subject, and in certain instances reducing the amount of FXI protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to prevent, treat, or ameliorate at least one symptom of a thromboembolic condition without a significant increase in a bleeding risk. Such thromboembolic conditions include deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition. Such symptoms include decreased blood flow through an affected vessel, death of tissue, and death.

The present embodiments provide methods, compounds, and compositions for treating, preventing, ameliorating, or slowing progression of retinitis pigmentosa (RP), such as autosomal dominant retinitis pigmentosa (AdRP) by administering a P23H rhodopsin specific inhibitor to a subject. The present embodiments provided herein are directed to compounds and compositions useful for treating, preventing, ameliorating, or slowing progression of retinitis pigmentosa (RP), such as autosomal dominant retinitis pigmentosa (AdRP). In certain embodiments, P23H rhodopsin inhibitors provided herein are allele-specific antisense compounds targeted to a P23H mutant allele that are capable of selectively inhibiting expression of P23H rhodopsin mutant protein to a greater extent than wild-type protein. In certain embodiments, administration of the allele specific antisense compounds in a subject having AdRP results in selective inhibition of P23H rhodopsin and allows the normal protein produced from the wild-type allele to maintain rod survival and function in the subject.