Antisense modulation of Her-4 expression

Details Antisense modulation of Her-4 expression Antisense modulation of Her-4 expression

2000-07-31

2001-07-03

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C435S006120, C435S455000, C536S023100, C536S024100, C536S024500

Reexamination Certificate

active

06255111

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Her-4. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Her-4. Such compounds have been shown to modulate the expression of Her-4.
BACKGROUND OF THE INVENTION
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals into intracellular signals that in turn modulate biochemical pathways. Examples of such extracellular signaling molecules include growth factors, cytokines, and chemokines. The cell surface receptors of these molecules and their associated signal transduction pathways are therefore one of the principal means by which cellular behavior is regulated. Because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation or functional mutations in the molecular components of signal transduction pathways. Consequently, considerable attention has been devoted to the characterization of these receptor proteins.
HER4 (also known as ErbB4 and p180/erbB4), a member of the EGF family of receptor/tyrosine kinases, is a protein that has been shown to play a complex role in several signal transduction pathways by forming homo- and heterodimers with other members of the EGF family depending on their concentrations and the concentration of particular ligands. The two groups of ligands specific to HER3 and HER4 are collectively termed neuregulins (NRGs) because of their demonstrated role in the nervous system. HER3 and HER4 function as the ligand binding receptors and HER2 along with EGFR are considered co-receptors and are recruited as partners to HER3 and HER4 upon ligand binding. (Burden and Yarden,
Neuron
, 1997, 18, 847-855).
HER4, first cloned in 1993, is predominantly expressed in breast carcinoma cell lines, and in normal skeletal muscle, heart, pituitary, brain, and the cerebellum (Plowman et al.,
Proc. Natl. Acad. Sci. U. S. A
., 1993, 90, 1746-1750). Disclosed in the European Patent Application EP 0 599 274 A1 are the recombinant polynucleotide encoding HER-4, antibodies to HER-4, plasmids encoding HER-4, host cells containing said plasmids and a HER-4 ligand (Plowman et al., 1994). Further disclosed in the PCT Publication WO 99/19488 are the HER-4 gene, antibodies to HER-4, vectors encoding HER-4, host cells expressing said vectors and bioassays for the detection of HER-4 (Klagsbrun et al., 1999).
HER4 has subsequently been shown to regulate the development of heart and neural tissues of the CNS (Carraway,
BioEssays
, 1996, 18, 263-266) and manifestations of altered HER4 regulation appear in both injury and disease states the most important being in the development of cancer. Cellular transformation and acquisition of the metastatic phenotype are the two main changes normal cells undergo during the progression to cancer and many studies have implicated HER4 in the development of the cancer phenotype. Overexpression of HER4 is correlated with decreased survival time in some cases of squamous cell carcinoma of the head and neck and Furger et al. showed that HER4 is overexpressed in granulosa cell tumors and that HRG/PE40, a toxic fusion protein, reduced tumor cell proliferation (Furger et al.,
Cancer Res
., 1998, 58, 1773-1778). Recently, it has been demonstrated that HER-3 and HER-4 are expressed at high levels in gastric cancers with three out of six gastric cancers expression HER-3 and four out of six gastric cancers overexpressing HER-4 (Kataoka et al.,
Life Sci
., 1998, 63, 553-564).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of HER4. Consequently, there remains a long felt need for agents capable of effectively inhibiting HER4 function. To date, strategies aimed at inhibiting HER4 function have involved the use of antibodies to HER2, fusion protein ligand toxins, and gene knockouts in mice and ribozymes.
Disclosed in the PCT Publication WO 99/23209 are enzymatic RNA molecules which cleave HER-4 mRNA and methods of using these ribozymes (Tang and Lippman, 1999).
Antibodies to HER2 have been used to disrupt the dimerization of HER4 with HER2 thereby inhibiting HER4 function (Fitzpatrick et al.,
FEBS Lett
., 1998, 431, 102-106). The fusion protein, HAR-TX beta 2 was found to be cytotoxic toward several carcinoma cell lines expressing the HER4 receptor while it did not induce cytotoxicity in cells expressing HER2 or HER3 (Siegall et al.,
J. Biol. Chem
., 1995, 270, 7625-7630). Finnaly, mice defective in HER4 showed impaired heart trabeculae resulting in embryonic death (Gassmann et al.,
Nature
, 1995, 378, 390-394).
It is evident that these targeting strategies are indirect and often inhibit multiple pathways or result in lethal modifications to the cell or organism. Therefore, antisense oligonucleotides provide a promising new pharmaceutical tool for the effective modification of the expression of specific genes.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding Her-4, and which modulate the expression of Her-4. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Her-4 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 Her-4 by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding Her-4, ultimately modulating the amount of Her-4 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Her-4. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Her-4” encompass DNA encoding Her-4, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to ield one or more mRNA species, and catalytic activity which ay be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of Her-4. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or dise

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