The invention relates to single-stranded RNA editing antisense oligonucleotides (AONs) for binding to a target RNA molecule for deaminating a target nucleotide, preferably an adenosine, present in the target RNA molecule and recruiting, in a cell, preferably a human cell, an enzyme with nucleotide deamination activity, preferably an ADAR enzyme, to deaminate the target nucleotide in the target RNA molecule. The AONs carry at least one methylphosphonate-modified internucleosidic linkage on a position that would render the AON more stable in comparison to an AON not carrying that methylphosphonate modification at that position.

This disclosure relates to modified single and dual guide RNAs having improved in vitro and in vivo activity in gene editing methods.

This disclosure relates to novel targets for angiogenic disorders. Novel oligonucleotides are also provided. Methods of using the novel oligonucleotides for the treatment of angiogenic disorders (e.g., preeclampsia) are also provided.

Programmable guide RNAs (gRNAs) play a central role in the CRISPR revolution sweeping biology and medicine by directing the function of a Cas protein effector to a target gene of choice. To achieve programmable control over regulatory scope, the activity of a conditional guide RNA (cgRNA) depends on the presence or absence of an RNA trigger, allowing for cell-selective regulation of CRISPR/Cas function. Unlike a standard gRNA, a cgRNA is programmable at multiple levels, with the target-binding sequence controlling the target of Cas activity (edit, silence, induce, or bind a gene of choice) and the trigger binding sequence controlling the scope of Cas activity. cgRNA mechanisms that are allosteric allow for independent design of the target and trigger sequences, providing the flexibility to select the regulatory target and scope independently. Disclosed herein are allosteric cgRNA mechanisms for both ON.fwdarw.OFF logic (conditional inactivation by an RNA trigger) and OFF.fwdarw.ON logic (conditional activation by an RNA trigger). Allosteric cgRNAs enable restriction of CRISPR/Cas function to a desired cell type, tissue, organ, or disease state. Allosteric cgRNAs provide a versatile platform for cell-selective and tissue-selective research tools, biotechnologies, diagnostics, and therapeutics.

The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the transthyretin (TTR) gene and methods of using such iRNA agents for treating or preventing TTR-associated ocular diseases.

The present invention provides an aptamer containing a sequence shown by the following formula (1) or formula (2): TABLE-US-00001 (1) GGGGCCUCC-N.sub.1-GGACYAAACC (2) GGGGCCUCC-N.sub.1-GGACWYAAACC
wherein N.sub.1 shows 3 to 24 bases in length, Y is C or U, and W is A or U (uracil is optionally thymine), wherein the aptamer binds to a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5).

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 specific-site specific/position specific, chirally-modified internucleotide linkages.

Synthetic αvβ6 integrin ligands of Formula I having serum stability and affinity for integrin αvβ6, which is a receptor expressed in a variety of cell types, are described. The described ligands are useful for delivering cargo molecules, such as RNAi agents or other oligonucleotide-based compounds, to cells that express integrin αvβ6, and thereby facilitating the uptake of the cargo molecules into these cells. Compositions that include αvβ6 integrin ligands and methods of use are also described. ##STR00001##

A compound for forming a conjugate with an active agent such as an oligonucleotide having a structure represented by Formula (321). The present disclosure also provides a corresponding conjugate. The conjugate of the present disclosure can specifically target hepatocytes, thereby effectively solve the problems associated with delivery of oligonucleotide drugs in vivo, and have low toxicity and excellent delivery efficiency while maintaining high stability for the delivered oligonucleotide. ##STR00001##

The invention provides compositions and methods for reducing expression of a target gene in a cell, involving contacting a cell with an isolated double stranded nucleic acid (dsNA) in an amount effective to reduce expression of a target gene in a cell. The dsNAs of the invention possess a single stranded extension (in most embodiments, the single stranded extension comprises at least one modified nucleotide and/or phosphate back bone modification). Such single stranded extended Dicer-substrate siRNAs (DsiRNAs) were demonstrated to be effective RNA inhibitory agents compared to corresponding double stranded DsiRNAs.