The present invention relates to a chirally-modified dsRNA agent capable of inhibiting the expression of a target gene. The sense and antisense strands of chirally-modified dsRNA agent independently or in combination comprises one or more site specificsite specific/position specific, chirally-modified internucleotide linkages.

A cross-linked nucleoside of the present invention is a compound represented by the formula (I) below. The cross-linked nucleoside of the present invention is usable as a substitute for a phosphorothioate-modified nucleic acid, which has a risk of, for example, accumulation in a specific organ. The cross-linked nucleoside also has excellent industrial productivity.

##STR00001##

The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one modified internucleoside linking group.

Disclosed herein are compounds including a nucleic acid (A), their preparation, and their use.

One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The sense strand of the dsRNA agent comprises at least one thermally destabilizing nucleotide, and at least one said thermally destabilizing nucleotide occurring at a site opposite to the seed region (positions 2-8) of the antisense strand; and the antisense strand of the dsRNA agent comprises at least two modified nucleotides that provide the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2′-OMe modification, wherein said modified nucleotides are separated by 11 nucleotides in length. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.

The instant disclosure provides RNA-modulating agents that function to recruit one or more small regulatory RNA molecules (e.g., miRNA molecules, Y RNAs, and siRNAs) to a target mRNA thereby modulating (e.g., inhibiting) the translation of the target mRNA or destabilizing the mRNA. Also provided are miRNA inhibitors and diagnostic agents that have improved binding affinity for their target miRNAs. Methods for using the RNA-modulating agents, miRNA inhibitors and diagnostic agents are also provided.

The present disclosure relates to an isolated compound including a phosphorothioated oligodeoxynucleotide (ODN) sequence conjugated to a short-activating RNA (saRNA) or an antisense oligonucleotide sequence (ASO), compositions of such a compound, and method of treatment of cancer and autoimmune diseases (with or without stimulating immune response), method of immune stimulation, method of activating CEBPA, and method of reducing activity of STAT transcription factor, by one of the disclosed compounds or compositions.

The present invention provides methods and compositions for reducing internalization and/or trafficking of tau in neuronal cells comprising contacting the cells with an effective amount of an LRP1 and/or SorLA antagonist. The invention further provides a method of treating or preventing Alzheimer's disease in a subject in need thereof, comprising administering to the subject an effective amount of an LRP1 and/or SorLA antagonist.

Disclosed herein are conditional siRNAs activatable by pro-hypertrophic RNA sequences and use thereof for treating conditions such as cardiac hypertrophy. The conditional siRNAs target calcineurin or HDAC2.

Compositions for providing stability to RNA may include a primary surfactant, and a metal-ion sequestrant. The primary surfactant may be a nonionic surfactant. The composition may be in a soluble liquid concentrate form and may be sufficient to provide shelf stability to RNA for one year at room temperature. Compositions for delivering RNA to a pest via exogenous, foliar application of the composition to a plant may comprise RNA; a primary surfactant; and a metal-ion sequestrant.