Mcgill University

Methylgene, Inc.

Hybridon, Inc.

Moshe Szyf

Eric Von Hofe

Shyam Ramchandani

Pascal Bigey

Ning Li

Sanjoy Bhattacharya

Paul Campbell

Yonghong Zhang

Sophie Petropoulos

Oligonucleotide inhibitors that inhibit expression of a mammalian MBD2/DNA demethylase (MBD2/dMTase) are provided. The oligonucleotide inhibitors can be used to inhibit the growth or proliferation of tumor cells in vitro and in vivo. The use of the oligonucleotide inhibitors in the treatment of cancer and methods of identifying potential target genes for cancer therapy or diagnosis using the oligonucleotide inhibitors are also provided.

Oligonucleotide inhibitors of MBD2/DNA demethylase and uses thereof

The present invention relates to a DNA demethylase enzyme having about 40 KDa, and wherein said DNA demethylase enzyme is overexpressed in cancer cells and not in normal cells. The present invention also relates to the therapeutic and diagnostic uses of the DNA demethylase.

DNA demethylase, therapeutic and diagnostic uses thereof

The invention provides novel mechanism-based inhibitors of DNA methyltransferase enzyme, and diagnostic and therapeutic uses for the same. The novel inhibitors according to the invention form stable, noncovalent complexes with DNA methyltransferase enzyme in a manner which is independent of S-adenosylmethionine.

Specific inhibitors of DNA methyl transferase

The invention provides recombinant nucleic acids comprising nucleic acid sequences from the genomic DNA methyltransferase gene. The invention further provides sequence information for such nucleic acid sequences. In addition, the invention provides antisense oligonucleotides complementary to special regions of the genomic DNA methyltransferase gene or its RNA transcript. Finally, the invention provides methods for using such antisense oligonucleotides as analytical and diagnostic tools, as potentiators of transgenic plant and animal studies and gene therapy approaches, and as potential therapeutic agents.

DNA methyltransferase genomic sequences and antisense oligonucleotides

The present invention relates to the interplay between the level of DNA methyltransferase and demethylase activities, to the role of the interplay between these levels on the proliferative, differentiated, tumorigenic and homeostatic state of the cell, and to the DNA methyltransferase and demethylase as therapeutic targets. The invention further relates to a reduction of the level of DNA methylation through inhibitors and antagonist in order to inhibit the excessive activity or hypermethylation of DNA MeTase in cancer cells to induce the original cellular tumor suppressing program, to turn on alternative gene expression programs, to provide therapeutics directed at a nodal point of regulation of genetic information, and to modulate the general level of methylase and demethylase enzymatic activity of a cell to permit specific changes in the methylation pattern of a cell.

Inhibition of DNA methyltransferase

The invention encompasses tumorigenicity-inhibiting antisense oligonucleotide sequences complementary to mRNA or double-stranded DNA that encodes mammalian DNA methyl transferase. It further encompasses methods for inhibiting tumorigenicity and pharmaceutical composition comprising the tumorigenicity-inhibiting antisense nucleotide.

Antisense olignucleotides having tumorigenicity-inhibiting activity

The invention encompasses tumorigenicity-inhibitiig antisense oligonucleotide sequences complementary to mRNA or double-stranded DNA that encodes mammalian DNA methyl transferase. It further encompasses methods for inhibiting tumorigenicity and pharmaceutical composition comprising the tumorigenicity-inhibiting antisense nucleotide.

Antisense oligonucleotides having tumorigenicity-inhibiting activity

The invention encompasses tumorigenicity-inhibiting antisense oligonucleotide sequences complementary to mRNA or double-stranded DNA that encodes mammalian DNA methyl transferase. It further encompasses methods for inhibiting tumorigenicity and pharmaceutical composition comprises the tumorigenicity-inhibiting antisense nucleotide.

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Cote St. Luc, Canada

Moshe Szyf