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Pharmaceutical compositions comprising anti-miRNA antisense oligonucleotides

A technology of oligonucleotides and single-stranded oligonucleotides, applied in the field of pharmaceutical compositions containing anti-microRNA antisense oligonucleotides, capable of solving problems such as low in vivo uptake and low in vivo stability

Inactive Publication Date: 2009-05-20
SANTARIS PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this antisense design is low in vivo uptake as well as low in vivo stability due to the 13 nucleotide DNA string in the anti-mir oligonucleotide

Method used

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  • Pharmaceutical compositions comprising anti-miRNA antisense oligonucleotides
  • Pharmaceutical compositions comprising anti-miRNA antisense oligonucleotides
  • Pharmaceutical compositions comprising anti-miRNA antisense oligonucleotides

Examples

Experimental program
Comparison scheme
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Embodiment approach

[0204] Further embodiments of the invention which may be combined with the above-described embodiments are shown in the claims and under the heading 'Further Embodiments'.

[0205] definition

[0206] The term 'nucleotide base' refers to nucleotides, such as DNA and RNA, and nucleotide analogs.

[0207] In the context of the present invention, the term "oligonucleotide" (or simply "oligomer") refers to a molecule formed by the covalent bond of 2 or more nucleotide bases. When used in the context of oligonucleotides of the invention (also known as single-stranded oligonucleotides), in one embodiment the term "oligonucleotide" may have, for example, 8-26 nucleotide bases Base, such as 10-26 nucleotide bases, such as 12-26 nucleotide bases. In a preferred embodiment, as detailed herein, the oligonucleotides of the invention have 8-17 nucleotide bases, such as 20-27 nucleotide bases, such as 8-16 nucleotide bases bases, for example 12-15 nucleotide bases in length.

[0208] In...

Embodiment 1

[0645] Embodiment 1: monomer synthesis

[0646] LNA monomeric building blocks and derivatives thereof are prepared according to published procedures and references cited therein, see, for example, WO 03 / 095467 A1 and D.S. Pedersen, C. Rosenbohm, T. Koch (2002) Preparation of LNA Phosphoramidites, Synthesis 6 , 802-808.

Embodiment 2

[0647] Example 2: Oligonucleotide Synthesis

[0648] Oligonucleotides were synthesized using the phosphoramidite method on an Expedite 8900 / MOSS synthesizer (multiple oligonucleotide synthesis system ( M multiple O ligonucleotides S Synthesis S system)) were synthesized on a 1 μmol or 15 μmol scale. For larger synthesis, use Oligo Pilot (GE Healthcare). At the end of the synthesis (with DMT), oligonucleotides were cleaved from the solid support using ammonia for 1-2 hours at room temperature and further deprotected at 65°C for 4 hours. Oligonucleotides were purified by reverse phase HPLC (RT-HPLC). After removal of the DMT-group, the oligonucleotides were characterized by AE-HPLC, RP-HPLC and CGE, and the molecular weight was further confirmed by ESI-MS. See below for more details.

[0649] Preparation of LNA-solid support:

[0650] Preparation of LNA succinyl half ester

[0651] 5'-O-Dmt-3'-hydroxy-LNA monomer (500 mg), succinic anhydride (12 eq.) and DMAP (1.2 ...

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Abstract

The invention provides pharmaceutical compositions comprising short single stranded oligonucleotides, of length of between 8 and 26 nucleobases which are complementary to human microRNAs selected from the group consisting of miR19b, miR21, miR122a, miR155 and miR375. The short oligonucleotides are particularly effective at alleviating miRNA repression in vivo. It is found that the incorporation of high affinity nucleotide analogues into the oligonucleotides results in highly effective anti-microRNA molecules which appear to function via the formation of almost irreversible duplexes with the miRNA target, rather than RNA cleavage based mechanisms, such as mechanisms associated with RNaseH or RISC.

Description

field of invention [0001] The present invention relates to pharmaceutical compositions comprising LNA-containing single-stranded oligonucleotides capable of inhibiting disease-inducing microRNAs, in particular human microRNAs miR-19b, miR-21, miR-122A, miR -155 and miR-375. Background of the invention [0002] MicroRNAs - novel regulators of gene expression [0003] MicroRNAs (miRNAs) are an abundant class of small endogenous RNAs that act as post-transcriptional regulators of gene expression by base-pairing with their target mRNAs. Mature miRNAs are sequentially processed from longer hairpin transcripts by the RNase III ribonucleases Drosha (Lee et al. 2003) and Dicer (Hutvagner et al. 2001, Ketting et al. 2001). According to the miRBase microRNA database version 7.1 as of October 2005 (Griffith-Jones 2004, Griffith-Jones et al. 2006), more than 3400 miRNAs have been annotated in vertebrates, invertebrates and plants to date and correspond to putative genes Many miRNAs ...

Claims

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Application Information

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IPC IPC(8): C12N15/11A61K31/712C07H21/00A61P3/06A61P3/10A61P31/14A61P35/00A61P9/10
CPCC12N15/113C12N2310/3231
Inventor J·埃尔门P·卡尼S·考皮宁
Owner SANTARIS PHARMA AS
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