Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject.

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.

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 inhibits activity of a pro-atrophy gene. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Provided herein are DNA aptamers targeting AXL receptor kinase. The DNA aptamers may comprise a thiophosphate backbone and be chemically modified. Further provided herein are methods of use thereof for the treatment of a disease or disorder, such as cancer.

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of APP RNA in a cell or animal, and in certain instances reducing the amount of APP 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 cognitive impairment, including a decline in memory and language skills, behavioral and psychological symptoms such as apathy and lack of motivation, gait disturbances and seizures, progressive dementia, and abnormal amyloid deposits.

The present disclosure relates to double-stranded oligonucleotides, including double-stranded oligonucleotides such as siRNAs, comprising a sense strand oligonucleotide and an antisense strand oligonucleotide, and wherein the antisense strand oligonucleotide comprises one or more nucleotide analogs of formula (I-A) which are neither the 5′-overhang nucleotide nor the 3′-overhang nucleotide of the said antisense strand oligonucleotide, and wherein a nucleotide analog of formula (I-A) is as described in the disclosure. Oligonucleotides containing these analogs have superior biological activity, for example, increased in vitro stability and improved in vivo potency especially improved off-target profiles. The improved oligonucleotides are useful for silencing (e.g., reducing or eradicating) the expression of a target gene.

The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.

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The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the complement component C3 gene (C3). The invention also relates to methods of using such RNAi agents to inhibit expression of a C3 gene and to methods of preventing and treating a C3-associated disorder, e.g., cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria (PNH), lupis nephritis (LN), bullous pemphigoid, pemphigus, e.g., pemphigus vulgaris (PV) and pemphigus foliaceus (PF), and C3 glomerulopathy.

Therapeutic oligonucleotides comprising pharmacokinetic (PK)-modifying anchors are provided. Methods for treating diseases or disorders comprising administering to a subject a therapeutic oligonucleotide comprising one or more PK-modifying anchors are provided.

Polynucleotide constructs are disclosed, that are potent activators of a STING-independent DNA sensing pathway (SIDSP), in which the DNA damage response protein DNA-PK is the sensor of the SIDSP, along with tire heat shock protein HSPA8 as a unique SIDSP target. The polynucleotide constructs of the disclosure are also potent activators of the cGAS-STING DNA sensing pathway. These pathways arm key components of the innate immune response that is important for antiviral immunity, contributes to specific autoimmune diseases, and mediate important aspects of antitumor immunity.