Antisense modulation of interferon gamma receptor 2

a technology of interferon gamma and receptor, which is applied in the direction of organic chemistry, peptide/protein ingredients, genetic material ingredients, etc., can solve the problems of limiting the attempts to modulate the process of ifn-gamma signaling, signaling on tumor growth, etc., and achieve the effect of modulating the expression of interferon gamma receptor 2

Inactive Publication Date: 2005-07-14
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding Interferon gamma receptor 2, and which modulate the expression of Interferon gamma receptor 2. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Interferon gamma receptor 2 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 Interferon gamma receptor 2 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

In addition, there are conflicting reports on the effects of IFN-gamma signaling on tumor growth in mice.
Attempts to modulate the process of IFN-gamma signaling have thus far been essentially limited to inhibition of IFN-gamma itself.

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

[0131] 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.

[0132] 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

[0133] 2′-fluoro ol...

example 2

Oligonucleotide Synthesis

[0162] 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.

[0163] 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. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0164] Alkyl phosphonate oligonucleotides are prepared as de...

example 3

Oligonucleoside Synthesis

[0171] 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.

[0172] 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.

[0173] 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 Interferon gamma receptor 2. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Interferon gamma receptor 2. Methods of using these compounds for modulation of Interferon gamma receptor 2 expression and for treatment of diseases associated with expression of Interferon gamma receptor 2 are provided.

Description

RELATED APPLICATIONS [0001] This application is a continuation of Ser. No. 10 / 819,244 filed Apr. 6, 2004; which is a continuation of Ser. No. 09 / 843,377 filed Apr. 26, 2001. This application is also a continuation-in-part of Ser. No. 10 / 702,817 filed Nov. 6, 2003; which is a continuation in part of Ser. No. 09 / 695,451 filed Oct. 24, 2000; which is a continuation-in-part of PCT / US99 / 13763 filed Jun. 17, 1999 which claims priority to U.S. application Ser. No. 09 / 106,038 filed Jun. 26, 1998, now issued as U.S. Pat. No. 6,007,995. This application is also a continuation-in-part of Ser. No. 10 / 703,864 filed Nov. 7, 2003; which is a continuation of Ser. No. 09 / 715,983 filed Nov. 20, 2000; which is a continuation-in-part of PCT / US00 / 40261 filed Jun. 21, 2000 which claims priority to U.S. application Ser. No. 09 / 344,521 filed Jun. 25, 1999, now issued as U.S. Pat. No. 6,100,090. This application is also a continuation-in-part of Ser. No. 10 / 622,801 filed Sep. 5, 2003; which is a continuatio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K48/00C07H21/02C12N15/113C12Q1/68
CPCA61K38/00C12N15/1138C12N2310/315C12N2310/321C12N2310/3341C12N2310/346C12N2310/341C12N2310/3525Y02P20/582
Inventor BENNETT, C.MONIA, BRETTMURRAY, SUSANBUTLER, MADELINEDEAN, NICHOLASCROOKE, ROSANNEGRAHAM, MARKZHANG, HONGFREIER, SUSANBAKER, BRENDAMARCUSSON, ERICWYATT, JACQUELINECOWSERT, LEXDOBIE, KENNETHWATT, ANDREW
Owner IONIS PHARMA INC
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