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Linkage modified gapped oligomeric compounds and uses thereof

a gapped oligomer and linkage technology, applied in the field of chemically modified oligonucleotides, can solve problems such as loss of normal function of the target rna, and achieve the effects of improving potency loss of normal function of the target rna, and improving selectivity for the target rna

Inactive Publication Date: 2014-10-09
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a type of molecule that can target and damage certain RNA molecules, which can cause issues in the body. The molecule contains a modified sugar that increases its affinity for RNA. This makes it easier for the molecule to attach to RNA and cause it to lose its function. The molecule can also be designed to be more potent and selective, meaning it can target and damage specific RNA molecules. The patent also mentions that the molecule can have an improved safety profile, meaning it is less toxic and less likely to cause inflammation. Overall, the patent describes a new way to create molecules that can target and damage RNA, potentially leading to new treatments for certain medical conditions.

Problems solved by technology

In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Method used

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  • Linkage modified gapped oligomeric compounds and uses thereof
  • Linkage modified gapped oligomeric compounds and uses thereof
  • Linkage modified gapped oligomeric compounds and uses thereof

Examples

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example 1

Synthesis of Nucleoside Phosphoramidites

[0351]The preparation of nucleoside phosphoramidites is performed following procedures that are illustrated herein and in the art such as but not limited to U.S. Pat. No. 6,426,220 and published PCT WO 02 / 36743.

example 2

Synthesis of Oligomeric Compounds

[0352]The oligomeric compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as alkylated derivatives and those having phosphorothioate linkages.

[0353]Oligomeric compounds: Unsubstituted and substituted phosphodiester (P═O) oligomeric compounds, including without limitation, oligonucleotides can be synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0354]In certain embodiments, phosphorothioate internucleoside linkages (P═S) are synthesized similar to phosphodiester internucleoside...

example 3

Isolation and Purification of Oligomeric Compounds

[0365]After cleavage from the controlled pore glass solid support or other support medium and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligomeric compounds, including without limitation oligonucleotides and oligonucleosides, are recovered by precipitation out of 1 M NH4OAc with >3 volumes of ethanol. Synthesized oligomeric compounds are analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis is determined by the ratio of correct molecular weight relative to the −16 amu product (+ / −32+ / −48). For some studies oligomeric compounds are purified by HPLC, as described by Chiang et al., J. Biol. Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material are generally similar to those obtained with non-HPLC purified material.

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Abstract

The present invention provides gapped oligomeric compounds. More particularly the gapped oligomeric compounds provided herein comprise at least one modified intemucleoside linkage in the gap region. Such gapped oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. 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.

Description

FIELD OF THE INVENTION[0001]The present invention pertains generally to chemically-modified oligonucleotides for use in research, diagnostics, and / or therapeutics.SEQUENCE LISTING[0002]The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled CHEM0084WOSEQ.txt, created Jul. 26, 2012, which is 268 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0003]Antisense compounds have been used to modulate target nucleic acids. Antisense compounds comprising a variety of chemical modifications and motifs have been reported. In certain instances, such compounds are useful as research tools, diagnostic reagents, and as therapeutic agents. In certain instances antisense compounds have been shown to modulate protein expression by binding to a target messenger RNA (mRNA) encoding the protein. In certain insta...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113
CPCC12N15/113C12N2310/11C12N2310/341C12N2310/312C12N2310/3125C12N2310/315C12N2310/316C12N2310/3231C12N2310/3341C12N2320/34C12N2310/314C12N2310/321C12N2310/3525C12N15/111C12N2310/351
Inventor OESTERGAARD, MICHAELPRAKASH, THAZHA P.SETH, PUNIT P.SWAYZE, ERIC E.
Owner IONIS PHARMA INC
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