Antisense modulation of BCAS1 expression

Details Antisense modulation of BCAS1 expression Antisense modulation of BCAS1 expression

2000-10-11

2002-05-28

LeGuyader, John L. (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S006120, C435S091100, C435S325000, C435S366000, C536S023100, C536S024310, C536S024330, C536S024500

Reexamination Certificate

active

06395544

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of BCAS1. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding BCAS1. Such compounds have been shown to modulate the expression of BCAS1.
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, which 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 20ql3. 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 20q13.2, one of which is associated with breast carcinomas (Collins et al.,
Proc. Natl. Acad. Sci. U. S. A
., 1998, 95, 8703-8708).
BCAS1 (breast cancer amplified sequence 1; also known as AIBC1 for amplified in breast cancer 1 and NABC1 for novel amplified in breast cancer 1) was isolated by positional cloning of chromosome 20. This gene was found to encode a 585 amino acid protein whose mRNA was found in highest abundance in brain and prostate. Hybridization of Northern blots of total RNA from breast cancer cell lines and cultured epithelial cells derived from mammoplasties revealed the BCAS1 transcript to be present in the amplified cell lines but not in normal epithelial cells (Collins et al.,
Proc. Natl. Acad. Sci. U. S. A
., 1998, 95, 8703-8708).
The pharmacological modulation of BCAS1 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 BCAS1 and strategies aimed at investigating BCAS1 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 BCAS1 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 BCAS1 expression.
The present invention provides compositions and methods for modulating BCAS1 expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding BCAS1, and which modulate the expression of BCAS1. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of BCAS1 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 BCAS1 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 BCAS1, ultimately modulating the amount of BCAS1 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding BCAS1. As used herein, the terms “target nucleic acid” and “nucleic acid encoding BCAS1” encompass DNA encoding BCAS1, 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 BCAS1. 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 BCAS1. 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 “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding BCAS1, regardless of the sequence(s) of such codons.
It is also known in the art that a translation termination codon

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