Novel oligonucleotides that are fully chemically stabilized are provided. Methods of using oligonucleotides that are fully chemically stabilized are also provided.

Provided are an siRNA for inhibiting the expression of the apolipoprotein C3 gene, and a pharmaceutical composition and a conjugate containing the siRNA. Each nucleotide in the siRNA is, respectively and independently, a modified or unmodified nucleotide; the siRNA contains a sense strand and an anti-sense strand; the sense strand includes nucleotide sequence I; nucleotide sequence I has the same length as the nucleotide sequence as shown in SEQ ID NO: 1, and not more than three nucleotides are different; the anti-sense strand contains nucleotide sequence II; and nucleotide sequence II has the same length as the nucleotide sequence as shown in SEQ ID NO: 2, and not more than three nucleotides are different. The siRNA provided by the present disclosure and the pharmaceutical composition and the conjugate thereof can effectively treat and/or prevent dyslipidemia.

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.

A method of increasing specificity of binding of a CRISPR-Cas protein-guide RNA complex to a selected target nucleic acid sequence is provided. The method comprises contacting a nucleic acid molecule comprising the selected target nucleic acid sequence with the complex comprising the CRISPR-Cas protein and the guide RNA, wherein the guide RNA comprises a complementarity region at the 5′ end of the guide RNA that binds to a complementary strand of the selected target nucleic acid sequence, wherein the guide RNA comprises at least one modified nucleic acid within the complementarity region; wherein the guide RNA complementarity region binds and directs the CRISPR-Cas protein (e.g. CRISPR/Cas9) to the selected target nucleic acid sequence, thereby increasing specificity of binding of the CRISPR-Cas protein-guide RNA complex to the selected target nucleic acid sequence. The modified nucleic acid may be a bridged nucleic acid, a deoxyribonucleic acid, or a 2-0-methyl RNA phosphonoacetate-modified crRNA, or a functional equivalent that improves specificity by inducing similar conformational changes in the CRISPR-Cas system. Guide RNAs, kits comprising a guide RNA together with a CRISPR-Cas protein, and complexes comprising a guide RNA and a CRISPR-Cas proteins are also provided.

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.

Novel artificial exosomes and methods for producing novel artificial exosomes are provided. Methods of delivering cargo molecules to a cell using artificial exosomes are also provided.

Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a cancer which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer.

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Described are 5′-cyclo-phosphonate modified nucleotides, and oligonucleotides, such as interference (RNAi) agents, containing 5′-cyclo-phosphonate modified nucleotides. The RNAi agents having either double-stranded or single-stranded oligonucleotides described herein comprising 5′cyclo-phosphonate modified nucleotides are useful in modulating gene expression as well as therapeutic, diagnostic, target validation, and genomic discovery applications. The RNAi agents and single-stranded antisense oligonucleotides comprising 5′-cyclo-phosphonate modified nucleotides are useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism. ##STR00001##

Among other things, the present disclosure provides designed DMD oligonucleotides, compositions, and methods of use GC thereof. In some embodiments, the present disclosure provides technologies useful for repairing mutant DMD transcripts by skipping exon 51 or exon 53, so that the transcript can be translated into an internally truncated but at least partially functional Dystrophin protein variant. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD) DMD transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as muscular dystrophy, including but not limited to Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.