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Antisense modulation of stearoyl-CoA desaturase expression

a technology of stearoylcoa and desaturase, which is applied in the direction of peptide/protein ingredients, application, metabolic disorders, etc., can solve the problems of untested strategies, ununderstandable control mechanisms that govern the conversion of saturated fatty acids to unsaturated fatty acids,

Inactive Publication Date: 2005-02-24
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] Further provided are methods of modulating the expression of stearoyl-CoA desaturase in cells or tissues comprising contacting the cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal,

Problems solved by technology

However, the control mechanisms that govern the conversion of saturated fatty acids to unsaturated fatty acids are not well understood.
However, these strategies are untested as therapeutic protocols.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2′-alkoxy amidites

[0147] 2′-Deoxy and 2′-methoxy beta-cyanoethyldiisopropyl phosphoramidites were purchased from commercial sources (e.g. Chemgenes, Needham Mass. or Glen Research, Inc. Sterling Va.). Other 2′-O-alkoxy substituted nucleoside amidites are prepared as described in U.S. Pat. No. 5,506,351, herein incorporated by reference. For oligonucleotides synthesized using 2′-alkoxy amidites, the standard cycle for unmodified oligonucleotides was utilized, except the wait step after pulse delivery of tetrazole and base was increased to 360 seconds.

[0148] Oligonucleotides containing 5-methyl-2′-deoxycytidine (5-Me-C) nucleotides were synthesized according to published methods [Sanghvi, et. al., Nucleic Acids Research, 1993, 21, 3197-3203] using commercially available phosphoramidites (Glen Research, Sterling Va. or ChemGenes, Needham Mass.).

2′-Fluoro amidites

2′-Fluorodeoxyadenosine amidites

[0149] 2′-fluoro oli...

example 2

Oligonucleotide Synthesis

[0178] Unsubstituted and substituted phosphodiester (P=O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 380B) using standard phosphoramidite chemistry with oxidation by iodine.

[0179] Phosphorothioates (P═S) are synthesized as for the phosphodiester oligonucleotides except the standard oxidation bottle was replaced by 0.2 M solution of 3H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the stepwise thiation of the phosphite linkages. The thiation wait step was increased to 68 sec and was followed by the capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (18 h), the oligonucleotides were purified by precipitating twice with 2.5 volumes of ethanol from a 0.5 M NaCl solution.

[0180] Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0181] Alkyl phosphonate oligonucleotides are prepared...

example 3

Oligonucleoside Synthesis

[0188] Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethyl-hydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligonucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P═O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.

[0189] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564, herein incorporated by reference.

[0190] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.

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Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of stearoyl-CoA desaturase. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding stearoyl-CoA desaturase. Methods of using these compounds for modulation of stearoyl-CoA desaturase expression and for treatment of diseases associated with expression of stearoyl-CoA desaturase are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of pending U.S. patent application Ser. No. 09 / 918,187, filed Jul. 30, 2001.BACKGROUND OF THE INVENTION [0002] Saturated fatty acids are known to be the precursors of unsaturated fatty acids in higher organisms. However, the control mechanisms that govern the conversion of saturated fatty acids to unsaturated fatty acids are not well understood. The relative amounts of different fatty acids have effects on the physical properties of membranes. Furthermore, regulation of unsaturated fatty acids is important because they play a role in cellular activity, metabolism and nuclear events that govern gene transcription. [0003] A critical committed step in the biosynthesis of mono-unsaturated fatty acids is the introduction of the first cis-double bond in the delta-9 position (between carbons 9 and 10). This oxidative reaction is catalyzed by stearoyl-CoA desaturase (SCD, also known as delta-9-desatura...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K45/06C07HC12N9/02C12N15/113
CPCA61K38/00A61K45/06C12N9/0083C12N15/1137C12N2310/11C12N2310/315C12N2310/321C12Y114/19001C12N2310/3341C12N2310/341C12N2310/346C12N2310/3525Y02P20/582A61P43/00A61P3/10
Inventor CROOKE, ROSANNEGRAHAM, MARK
Owner IONIS PHARMA INC
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