Isis Pharmaceuticals, Inc.

Trius Therapeutics, Inc.

Vickie L Brown-Driver

David J Ecker

Jacqueline R Wyatt

Kevin P Anderson

Ronnie C Hanecak

Timothy A Vickers

John M Finn

Robert Haselbeck

Karen Joy Shaw

Mark Hilgers

Mark Stidham

Kedar Gc

C Frank Bennett

Ming-Yi Chiang

Susan M Freier

Phillip Dan Cook

Lex M Cowsert

Stanley T Crooke

Kenneth G Draper

Yogesh S Sanghvi

Thomas W Bruice

Ravi Jain

Christopher K Mirabelli

Peter W Davis

Ian Popoff

Jean Louis Imbach

The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a &#x3b2;-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

Identification and application of antibiotic synergy

Compounds, compositions and methods are provided for modulating the expression of transthyretin. The compositions comprise oligonucleotides, targeted to nucleic acid encoding transthyretin. Methods of using these compounds for modulation of transthyretin expression and for diagnosis and treatment of diseases and conditions associated with expression of transthyretin are provided.

Modulation of transthyretin expression

The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.

Method for identifying drug-sensitizing antisense DNA fragments and use thereof

Modified oligonucleotides having a GGG motif sequence and a sufficient number of flanking nucleotides to modulate the telomere length of a chromosome are provided. Methods of modulating telomere length of a mammalian chromosome in vitro and in vivo are also provided, as are methods for inhibiting the division of a malignant mammalian cell and for modulating the effects of cellular aging.

Modulation of telomere length by oligonucleotides having a G-core sequence

Antisense compounds, compositions and methods are provided for modulating the expression of E2F transcription factor 1. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding E2F transcription factor 1. Methods of using these compounds for modulation of E2F transcription factor 1 expression and for treatment of diseases associated with expression of E2F transcription factor 1 are provided.

Antisense inhibition of e2f transcription factor 1 expression

Oligonucleotides having a conserved G4 core sequence

Methods useful for the determination of oligomers which have specific activity for a target molecule from a pool of primarily randomly assembled oligomers are provided. The disclosed methods involve repeated syntheses of increasingly simplified sets of oligomers coupled with selection procedures for determining oligomers having the highest activity. Freedom from the use of enzymes allows the application of these methods to any molecules which can be oligomerized in a controlled fashion.

Methods for synthetic unrandomization of oligomer fragments

Compositions and methods are provided for the treatment and diagnosis of herpesvirus infections. In accordance with preferred embodiments, oligonucleotides are provided which are specifically hybridizable with RNA or DNA deriving from a herpesvirus gene corresponding to one of the open reading frames UL5, UL8, UL9, UL20, UL27, UL29, UL30, UL42, UL52 and IE175 of herpes simplex virus type 1. The oligonucleotide comprises nucleotide units sufficient in identity and number to effect said specific hybridization. In other preferred embodiments, the oligonucleotides are specifically hybridizable with a translation initiation site, a coding region or a 5'-untranslated region. Methods of treating animals suspected of being infected with herpesvirus comprising contacting the animal with an oligonucleotide of the invention are disclosed. Methods for treatment of infections caused by herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, human herpes virus 6, Epstein Barr virus or varicella zoster virus are disclosed.

Oligonucleotide therapies for modulating the effects of herpes viruses

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San Diego, CA, United States of America

Vickie L Brown-Driver