Antisense modulation of BTAK expression

Details Antisense modulation of BTAK expression Antisense modulation of BTAK expression

2000-09-11

2002-03-05

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C536S023100, C536S024100, C536S024310, C536S024500, C514S04400A, C435S006120, C435S091100, C435S320100, C435S325000, C435S366000

Reexamination Certificate

active

06352858

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of BTAK. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding BTAK. Such compounds have been shown to modulate the expression of BTAK.
BACKGROUND OF THE INVENTION
Breast cancer emerges by a multi-step process broadly equated to transformation of normal cells via hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular mechanisms, that lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies of prevention and treatment.
Genetic analysis of breast cancer samples demonstrates that tumor development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumor suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the protein seems to be specific for certain types of breast cancer. Two chromosomal loci with a high frequency of amplification associated with breast cancer are 17q22-q24 and 20q13. Initial comparative genomic hybridization studies showed increased copy number involving 20q13 in 40% of breast cancer cell lines and in 18% of primary breast tumors (Kallioniemi et al.,
Proc. Natl. Acad. Sci. U. S. A.,
1994, 91, 2156-2160). Since then, other studies have revealed increased copy numbers in the 20q13 region in greater than 25% of a variety of cancers.
Recently, several amplified genes have been mapped to chromosome 20q13, one of which is associated with breast carcinomas (Sen et al.,
Oncogene,
1997, 14, 2195-2200).
BTAK (breast tumor amplified kinase; also known as STK15 for serine/threonine kinase 15, aurora2, AIK, and IPL1-related kinase) is a serine threonine centrosome-associated kinase first cloned from the 20q13 amplicon and found to be overexpressed in breast tumor cell lines (Sen et al.,
Oncogene,
1997, 14, 2195-2200). Disclosed in U.S. Pat. Nos. 5,962,312 and 5,972,676 are the nucleic acid and polypeptide sequence of BTAK (Plowman and Mossie, 1999; Plowman and Mossie, 1999).
Subsequently, it has been demonstrated that BTAK is amplified in human colorectal cancers (Bischoff et al.,
Embo J.,
1998, 17, 3052-3065), as well as in ovarian, prostate, neuroblastoma and cervical cancers (Zhou et al.,
Nat. Genet.,
1998, 20, 189-193). Additionally, high expression of BTAK mRNA was detected in tumor cell lines without evidence of gene amplification.
It has also been shown that BTAK is involved in the induction of centrosome duplication (Farruggio et al.,
Proc. Natl. Acad. Sci. U. S. A.,
1999, 96, 7306-7311; Giet and Prigent,
J. Cell Sci.,
1999, 112, 3591-3601; Kimura et al.,
J. Biol. Chem.,
1997, 272, 13766-13771; Tanaka et al.,
Cancer Res.,
1999, 59, 2041-2044; Zhou et al.,
Nat. Genet.,
1998, 20, 189-193). Centrosomes are structures which maintain genomic stability through the establishment of bipolar spindles during cell division. This ensures the equal segregation of replicated chromosomes to the two daughter cells. Deregulated duplication and distribution of centrosomes has been implicated in chromosomal abnormalities leading to aneuploidy, and cellular transformation. Taken together, these data suggest that centrosome deregulation may be the mechanism by which BTAK effects oncogenic transformation in certain cell types.
The pharmacological modulation of BTAK activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in pathological conditions such as breast cancer.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of BTAK and strategies aimed at investigating BTAK function have involved the use of antibodies for the localization of the protein. Consequently, there remains a long felt need for agents capable of effectively inhibiting BTAK function.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of BTAK expression.
The present invention provides compositions and methods for modulating BTAK expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding BTAK, and which modulate the expression of BTAK. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of BTAK 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 BTAK 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 BTAK, ultimately modulating the amount of BTAK produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding BTAK. As used herein, the terms “target nucleic acid” and “nucleic acid encoding BTAK” encompass DNA encoding BTAK, 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 yield one or more mRNA species, and catalytic activity which may 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 BTAK. 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 disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding BTAK. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “s

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