Antisense modulation of microsomal triglyceride transfer protein expression

an anti-sense and triglyceride technology, applied in the field of anti-sense modulation of microsomal triglyceride transfer protein expression, can solve the problems of no known therapeutic agents that effectively inhibit the synthesis, premature atherosclerosis, etc., and achieve the effect of modulating the expression of microsomal triglyceride transfer protein

Inactive Publication Date: 2005-08-18
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding microsomal triglyceride transfer protein, and which modulate the expression of microsomal triglyceride transfer protein. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of microsomal triglyceride transfer protein in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of microsomal triglyceride transfer protein by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.

Problems solved by technology

Elevated plasma lipid levels cause premature atherosclerosis.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of microsomal triglyceride transfer protein.

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

[0120] 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.

[0121] 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

[0122] 2′-fluoro ol...

example 2

Oligonucleotide Synthesis

[0150] 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.

[0151] 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.

[0152] Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0153] Alkyl phosphonate oligonucleotides are prepare...

example 3

Oligonucleoside Synthesis

[0160] Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethylhydrazo 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.

[0161] 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.

[0162] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.

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PUM

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Abstract

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

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] The present application is a continuation of co-pending application Ser. No. 09 / 917,963 filed on Jul. 30, 2001.BACKGROUND OF THE INVENTION [0002] Triglycerides are one of the most efficient storage forms of free energy. Because of their insolubility in biological fluids, their transport between cells and tissues requires that they be assembled into lipoprotein particles. Genetic disruption of the lipoprotein assembly / secretion pathway leads to several human disorders associated with malnutrition and developmental abnormalities. In contrast, patients displaying inappropriately high rates of lipoprotein production display increased risk for the development of atherosclerotic cardiovascular disease (Davis, Biochim. Biophys. Acta, 1999, 1440, 1-31). [0003] The mammalian lipoprotein assembly / secretion pathway requires 2 components: apolipoprotein B (ApoB, an amphipathic protein) and a lipid transfer protein (microsomal triglyceride transfer p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00C12N15/113
CPCA61K38/00C12N15/113C12N2310/315C12N2310/321C12N2310/3341C12N2310/346C12N2310/341C12N2310/3525Y02P20/582
Inventor CROOKE, ROSANNEGRAHAM, MARK
Owner IONIS PHARMA INC
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