In one aspect, the invention relates to a method of loading exosomes with oligonucleotide cargo, by incubating an oligonucleotide comprising one or more hydrophobic modifications with a population of exosomes for a period of time sufficient to allow loading of the exosomes with the oligonucleotide. Exosomes loaded with hydrophobically modified oligonucleotide cargo, and uses thereof, are also provided.

The invention relates generally to tRNA-based effector molecules having a non-naturally occurring modification and methods relating thereto.

The present invention relates to ocular administration of sd-rxRNA and rxRNAori molecules.

An isolated or purified antisense oligomer with a modified backbone structure for modifying pre-mRNA splicing in the parkin gene transcript or part thereof.

The present disclosure includes the use of a miRNA inhibitor for treating a disease or condition associated with a decreased level of SIRT1, PGC-1α, CD36, LRRK2, NRG1, STMN2, VLDLR, NRXN1, GRIA4, NXPH1, PSD-95, and/or synaptophysin protein or SIRT1, PGC-1α, CD36, LRRK2, NRG1, STMN2, VLDLR, NRXN1, GRIA4, NXPH1, PSD-95, and/or synaptophysin gene expression. In some aspects, the miRNA inhibitor can be used to treat a disease or condition associated with an increased level of caspase-3 protein or gene expression. The miRNA inhibitor useful for the present disclosure can inhibit miR-485 expression and/or activity, which in turn can increase the level of SIRT1, PGC-1α, CD36, LRRK2, NRG1, STMN2, VLDLR, NRXN1, GRIA4, NXPH1, PSD-95, and/or synaptophysin protein or gene expression; and/or can decrease the level of caspase 3 protein or gene expression.

The present disclosure provides for antibody-oligonucleotide conjugates, methods of preparation thereof, and methods of use thereof. Also provided are related compounds, compositions and kits.

In certain aspects, the present invention provides methods for inducing a stable gene modification of a target nucleic acid via homologous recombination in a primary cell, such as a primary blood cell and/or a primary mesenchymal cell. In certain other aspects, the present invention provides methods for enriching a population of genetically modified primary cells having targeted integration at a target nucleic acid. The methods of the present invention rely on the introduction of a DNA nuclease such as a Cas polypeptide and a homologous donor adeno-associated viral (AAV) vector into the primary cell to mediate targeted integration of the target nucleic acid. Also provided herein are methods for preventing or treating a disease in a subject in need thereof by administering to the subject any of the genetically modified primary cells or pharmaceutical compositions described herein to prevent the disease or ameliorate one or more symptoms of the disease.

The present invention relates to a compound of formula (II) or (IIb) Wherein X, Y, R.sup.x, R.sup.y, R.sup.5 and Nu are as defined in the description and in the claims. The compound of formula (II) can be used in the manufacture of oligonucleotides. ##STR00001##

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.

Disclosed herein are methods for preparing compositions containing oligonucleotides. Methods of this disclosure involve subjecting an aqueous solution of a oligonucleotide to ultrafiltration/diafiltration (UF/DF) in order to form a retentate containing the oligonucleotide, where the ultrafiltration/diafiltration (UF/DF) is carried out using an aqueous buffer solution containing one or more salts. Also disclosed herein are oligonucleotide-containing compositions obtained by these methods.