This disclosure relates to novel modified oligonucleotides. Novel modified siRNA are also provided.

This disclosure relates to novel modified oligonucleotides. Novel modified siRNA are also provided.

The present invention relates to guide RNAs having chemical modifications and their use in CRISPR-Cas systems. The chemically modified guide RNAs have enhanced specificity for target polynucleotide sequences. The present invention also relates to methods of using chemically modified guide RNAs for cleaving or nicking polynucleotides, and for high specificity genome editing.

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.

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Recent advancements in LNA oligonucleotides include the use of amine linkers to link an LNA antisense oligonucleotide to a conjugate group. For example please see WO2014/I 18267. The present invention originates from the identification of a problem when de-protecting LNA oligonucleotides which comprise an aliphatic amine group and DMF protected LNA G nucleoside, which results in the production of a +28 Da impurity. This problem is solved by using acyl protection groups on the exocyclic nitrogen of the LNA-G residue, rather than the standard DMF protection group.

The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the HMGB 1 gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a HMGB1 gene and to methods of N preventing and treating an HMGB1-associated disorder, e.g., metabolic disorder or non-alcholic fatty liver disease, e.g., non-alcoholic steatohepatitis (NASH).

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Glial cell derived neurotrophic factor (GDNF), in particular, by targeting natural antisense polynucleotides of Glial cell derived neurotrophic factor (GDNF). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of GDNF.

The present invention relates to guide RNAs having chemical modifications and their use in CRISPR-Cas systems. The chemically modified guide RNAs have enhanced specificity for target polynucleotide sequences. The present invention also relates to methods of using chemically modified guide RNAs for cleaving or nicking polynucleotides, and for high specificity genome editing.

The present disclosure pertains generally to chemically-modified oligonucleotides for use in research, diagnostics, and/or therapeutics. In certain embodiments, the present disclosure describes compounds and methods for the modulation of a target nucleic acid. In certain embodiments, the present disclosure describes compounds and methods for the modulation of Apoliprotein C-III expression.

Therapeutic oligonucleotides comprising pharmacokinetic (PK)-modifying anchors are provided. Methods for treating diseases or disorders comprising administering to a subject a therapeutic oligonucleotide comprising one or more PK-modifying anchors are provided.