Ionis Pharmaceuticals, Inc.

Cold Spring Harbor Laboratory

Lonis Pharmaceuticals, Inc.

Xue-hai Liang

Stanley T Crooke

Wen Shen

Punit P Seth

Michael T Migawa

Michael Oestergaard

Eric E Swayze

C Frank Bennett

David L Spector

William John Drury, Iii

Brooke A Anderson

The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.

Modified compounds and uses thereof

In certain embodiments, the present disclosure provides compounds and methods of increasing the amount or activity of a target protein in a cell. In certain embodiments, the compounds comprise a translation suppression element inhibitor. In certain embodiments, the translation suppression element inhibitor is a uORF inhibitor. In certain embodiments, the uORF inhibitor is an antisense compound.

Compounds and methods for the modulation of proteins

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.

Linkage modified oligomeric compounds and uses thereof

In certain embodiments, the present disclosure provides methods comprising contacting a cell with a compound comprising a modified oligonucleotide complementary to a nucleic acid transcript. In certain such embodiments, the modified oligonucleotide does not interact or interacts poorly with a mRNP complex or granule. In certain such embodiments the modifications and/or motifs of the modified oligonucleotide do not promote interaction with a mRNP complex or granule. In certain embodiments, the present disclosure provides methods comprising contacting a cell with a compound comprising a modified oligonucleotide thereby reducing the size or amount of protein aggregation in the cell. In certain such embodiments, the protein aggregate is a mRNP granule. In certain such embodiments, the modifications and/or motifs of the modified oligonucleotide promote interaction with a protein aggregate, such as a mRNP granule, that results in disruption of the protein aggregate.

Compositions and methods for modulation of protein aggregation

In certain embodiments, the present disclosure provides compounds and methods for increasing the antisense activity of an antisense compound in a cell. In certain embodiments, the present disclosure provides methods for identifying antisense compounds having high activity. In certain embodiments, the present disclosure provides methods for identifying antisense compounds that bind to enhancer or repressor proteins.

Compounds and methods for increasing antisense activity

The present invention provides compounds and methods for modulating target nucleic acids found in organelles or sub-organelles of cells. The invention includes, but is not limited to compounds and methods that modulate target nucleic acids in a sub-nuclear organelle, such as the nucleolus and/or a cajal body. In certain embodiments, the cell is in an animal.

Compounds and methods for modulating target nuclear and sub-nuclear nucleic acid molecules in cells and animals

The present invention provides compounds and methods for competitive modulation of microRNAs. Such compounds and methods have profound effects on cells. MicroRNAs (microRNAs), are small (approximately 18-24 nucleotides in length), non-coding RNA molecules encoded in the genomes of plants and animals. In certain instances, microRNAs regulate the expression of genes by binding to the 3'-untranslated regions (3&#x2032;-UTR) of specific mRNAs. More than 1000 different microRNAs have been identified in plants and animals.

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Del Mar, CA, United States of America

Xue-hai Liang