Hybridon, Inc.

Ruiwen Zhang

Sudhir Agrawal

Robert B Diasio

Jiandong Chen

The invention provides methods to activate tumor suppressors. The invention further provides antisense oligonucleotides complementary to a portion of the MDM2-encoding RNA and methods for using such antisense oligonucleotides as analytical and diagnostic tools, as potentiators of transgenic animal studies and for gene therapy approaches, and as potential therapeutic agents. The invention also provides methods to augment and synergistically activate a tumor suppressor in conjunction with the use of a DNA-damage inducing agent. The invention further provides in vitro and in vivo models to evaluate the therapeutic effectiveness of a recently identified anti-human-MDM2 antisense oligonucleotide in the treatment of human colorectal cancers.

MDM2-specific antisense oligonucleotides

Disclosed is a method of down-regulating the expression of a gene in an animal, wherein a pharmacological formulation comprising a chimeric oligonucleotide complementary to the gene is orally administered to an animal. The oligonucleotide administered has at least one phosphorothioate internucleotide linkage and at least one alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, phosphoramidite, phosphate ester, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester internucleotide linkage.

Method of down-regulating gene expression

The invention provides methods to activate tumor suppressors. The invention further provides antisense oligonucleotides complementary to a portion of the MDM2-encoding RNA and methods for using such antisense oligonucleotides as analytical and diagnostic tools, as potentiators of transgenic animal studies and for gene therapy approaches, and as potential therapeutic agents. The invention also provides methods to augment and synergistically activate a tumor suppressor in conjunction with the use of a DNA-damage inducing agent.

Disclosed is a method of down-regulating the expression of a gene in an animal, wherein a pharmalogical formulation comprising an oligonucleotide complementary to the gene is orally administered to an animal. The oligonucleotide administered has non-phosphodiester internucleotide linkages and includes at least one 2'-substituted ribonucleotide, the oligonucleotide inhibiting the expression of a product of the gene, thereby down-regulating the expression of the gene.

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Marietta, GA, United States of America

Ruiwen Zhang