Dicerna Pharmaceuticals, Inc.

Novo Nordisk Healthcare Ag

Weimin Wang

Naim Nazef

Bob Dale Brown

Henryk T Dudek

Cheng Lai

Qingyi Li

Natalie Wayne Pursell

Utsav Saxena

Venkata Krishnamurthy

Boyoung Kim

Rachel Storr

Bob D Brown

Natalie Pursell

Disclosed herein are oligonucleotides, such as nucleic acid inhibitor molecules, having a 4'-phosphate analog and methods of using the same, for example, to modulate the expression of a target gene in a cell. The phosphate analogs are bound to the 4′-carbon of the sugar moiety (e.g., a ribose or deoxyribose or analog thereof) of the 5′-terminal nucleotide of an oligonucleotide. Typically, the phosphate analog is an oxymethylphosphonate, where the oxygen atom of the oxymethyl group is bound to the 4′-carbon of the sugar moiety or analog thereof.

4'-phosphate analogs and oligonucleotides comprising the same

Disclosed herein are glutathione-sensitive oligonucleotides and methods of using the same. Any oligonucleotide of interest may be modified with a glutathione-sensitive moiety, including oligonucleotides used for in vivo delivery, such as nucleic acid inhibitor molecules. Typically, the glutathione-sensitive moiety is used to reversibly modify the 2'-carbon of a sugar moiety in one or more nucleotides in the oligonucleotide, although other carbon positions may also be modified with the glutathione-sensitive moiety. Also disclosed are glutathione-sensitive nucleotide and nucleoside monomers, including glutathione-sensitive nucleoside phosphoramidites that can be used, for example, in standard oligonucleotide synthesis methods. In addition, glutathione-sensitive nucleotide and nucleoside monomers without a phosphoramidite can be used therapeutically, for example, as anti-viral agents.

Compositions comprising reversibly modified oligonucleotides and uses thereof

Provided herein are double-stranded nucleic acid inhibitor molecules having a sense strand with a stem loop structure and an antisense strand, where the stem portion of the stem loop structure contains one or more T-increasing nucleotides. Also provided are methods and compositions for reducing target gene expression and methods and compositions for treating a disease of interest.

Double-stranded nucleic acid inhibitor molecules modified with Tm-increasing nucleotides

This disclosure relates to oligonucleotides, compositions and methods useful for reducing LDHA expression, particularly in hepatocytes.

Methods and compositions for inhibiting expression of LDHA

Disclosed herein are oligonucleotides, such as nucleic acid inhibitor molecules, having a 4'-phosphate analog and methods of using the same, for example, to modulate the expression of a target gene in a cell. The oligonucleotide of the disclosure comprises a 5&#x2032;-terminal nucleotide represented by Formula III: wherein R, R, B, Xand Y are as defined in the specification. The phosphate analogs are bound to the 4&#x2032;-carbon of the sugar moiety (e.g., a ribose or deoxyribose or analog thereof) of the 5&#x2032;-terminal nucleotide of an oligonucleotide. Typically, the phosphate analog is an oxymethylphosphonate, where the oxygen atom of the oxymethyl group is bound to the 4&#x2032;-carbon of the sugar moiety or analog thereof. An illustrative 5&#x2032;-terminal nucleotide of an oligonucleotide of the disclosure may have the following chemical structure: 

Disclosed herein are glutathione-sensitive oligonucleotides and methods of using the same. The glutathione-sensitive oligonucleotides may comprise at least one nucleotide represented by Formula I: wherein A, B, I, J, L, R, R, R, R, U, U, W, and X are as defined in the specification. An illustrative glutathione-sensitive oligonucleotide of the disclosure may have the following chemical structure: Any oligonucleotide of interest may be modified with a glutathione-sensitive moiety, including oligonucleotides used for in vivo delivery, such as nucleic acid inhibitor molecules. Also disclosed are glutathione-sensitive nucleotide and nucleoside monomers, including glutathione-sensitive nucleoside phosphoramidites that can be used, for example, in standard oligonucleotide synthesis methods. In addition, glutathione-sensitive nucleotide and nucleoside monomers without a phosphoramidite can be used therapeutically, for example, as anti-viral agents.

Growing community of inventors

Newton, MA, United States of America

Weimin Wang