Roche Innovation Center Copenhagen A/s

Santaris Pharma A/s

Hoffmann-la Roche Inc.

Enzon Pharmaceuticals, Inc.

F. Hoffmann-la Roche Ag

Christoph Rosenbohm

Troels Koch

Daniel Sejer Pedersen

Signe M Christensen

Henrik Frydenlund Hansen

Majken Westergaard

Charlotte Albaek Thrue

Miriam Frieden

Nikolaj Dam Mikkelsen

Jacob Ravn

Jesper Wengel

Dennis Jul Hansen

Nanna Albaek

Michael Meldgaard

Mads Detlef Sørensen

Peter Hagedorn

Ellen Marie Straarup

Nanna Albæk

Marcel Gubler

Sabine Sewing

Margit Wissenbach

Annie Moisan

Jens Bo Rode Hansen

Jens Bo Hansen

Mads Detlef Sorensen

Lene Sonderbye Kjaerulff

Marlene Asklund

Bo Hansen

Joerg Hoernschemeyer

Charlotte Thrue

Daniel Pedersen

Jacob Jensen

Lene Sønderbye Kjærulff

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/I18267. 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.

LNA-G process

The present invention relates to the field of oligonucleotide conjugates and to methods of synthesis thereof. In the present method a low-water content solvent environment allows a more efficient conjugation, reducing the amount of conjugate moiety needed and increasing the conjugation reaction speed.

Oligonucleotide conjugation process

This invention generally relates to the field of phosphoramidite derivatives. In particular, the invention relates to N-Acetylgalactosamine phosphoramidite molecules and to conjugates of nucleic acid molecules with N-Acetylgalactosamine containing molecules. Also provided are methods for preparation of these molecules and possible uses thereof, in particular in medicine.

GalNAc phosphoramidites, nucleic acid conjugates thereof and their use

The invention relates to a method of identifying stereodefined phosphorothioate oligonucleotide variants with reduced toxicity by creating and screening libraries of stereodefined chiral phosphorothioate variants for compounds with reduced toxicity, either in vitro or in vivo.

Chiral library screen

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

Antisense design

Amino-LNA, thio-LNA and alpha-L-oxy-LN

The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as &#x3b1;--oxy-LNA, amino-LNA, &#x3b1;--amino-LNA, thio-LNA, &#x3b1;--thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilising intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues. 

Synthesis of locked nucleic acid derivatives

Short oligonucleotides directed against the Apo-B100 gene are provided for modulating the expression of Apo-B100. Methods of using these compounds for modulation of Apo-B100 expression and for the treatment of diseases associated with Apo-B100 expression are provided. The oligonucleotides comprise deoxyribonucleosides and locked nucleic acids.

RNA antagonist compounds for the inhibition of Apo-B100 expression

The present disclosure concerns LNA oligonucleotides having a (sub)sequence of the general formula 5'-()(T)CAtccatggCA()(c)-3&#x2032;, and preferably of the general formula 5&#x2032;-TCAatccatggCAc-3&#x2032;, wherein capital letters designate an LNA nucleotide analogue selected from &#x3b2;-D-oxy-LNA, &#x3b2;-D-thio-LNA, &#x3b2;-D-amino-LNA and &#x3b1;-L-oxy-LNA, small letters designate a deoxynucleotide, and underline designates either an LNA nucleotide analogue as defined above or a deoxynucleotide. Such LNA oligonucleotides exhibit surprisingly good properties with respect to inhibition of the expression of Survivin by means of an anti-sense mechanism, and thereby lead to reduction or inhibition of tumor development in vivo. The LNA oligonucleotides are superior to other LNA oligonucleotides targeting Surviving mRNA measured by functional read outs such as apoptosis induction and proliferation inhibition, and is potent in down-regulating Survivin mRNA and protein in transfected cancer cell lines, and induce apoptosis in combination with Taxol superior compared to other LNA oligonucleotides.

LNA oligonucleotides and the treatment of cancer

Methods are described for the synthesis of Locked Nucleic Acid (LNA) derivatives using certain nitrogen-containing nucleophiles.

Growing community of inventors

Birkerød, Denmark

Christoph Rosenbohm