Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2000-11-17
2002-03-12
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S325000, C435S006120, C435S091100, C536S023100, C536S024300, C536S024310, C536S024330, C536S024500
Reexamination Certificate
active
06355482
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Integrin beta 4 binding protein. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Integrin beta 4 binding protein. Such compounds have been shown to modulate the expression of Integrin beta 4 binding protein.
BACKGROUND OF THE INVENTION
Cell adhesive contacts are critical for the development and maintenance of multicellular organisms. These contacts are mediated by cell adhesion molecules (CAMs), a versatile class of compounds expressed on the cell surface. Cells adhere to one another and to extracellular substrates through the concerted action of a variety of CAMs, which act as both receptors and ligands on opposing cells.
Integrins, one class of CAMs, play important roles in cell migration, cell anchorage to substrates and cytoadhesion signaling pathways (Akiyama,
Hum. Cell,
1996, 9, 181-186). Integrins are heterodimeric cation-dependent membrane glycoproteins composed of an alpha and beta subunit and have been found in all tissues examined. Structurally integrins consist of a large extracellular domain, a transmembrane domain and a smaller cytoplasmic domain. It is the extracellular domain of the integrin that acts as a receptor for various matrix proteins, while the cytoplasmic domain has been shown to interact with actin filaments of the cytoskeleton, thereby mediating signaling cascades (LaFlamme et al.,
Matrix Biol.,
1997, 16, 153-163). Interference with integrin signaling is associated with a variety of effects, including regulation of gene expression and mitotic progression.
The integrin beta 4 (ITGB4) subunit is known to associate with the alpha 6 subunit to form the laminin receptor. In addition, high levels of the integrin beta 4 subunit are found in epithelial, Schwann cells and multiple tumor types. Levels of integerin beta 4 are also highly enriched in hemidesmosomes, dense cytoplasmic plaques that mediate the attachment of the stratified squamous epithelium to the underlying dermis connected via the extracellular anchoring filaments of the basement membrane. One specialized domain found in the cytoplasmic region of ITGB4, characterized by the presence of fibronectin type III modules, is believed to be responsible for mediating ITGB4 signaling events.
Using a yeast two-hybrid system to identify cellular proteins that interact with this domain, Biffo et al. isolated a human epithelial cell cDNA encoding an integrin beta 4 binding protein, p27BBP (Biffo et al.,
J. Biol. Chem.,
1997, 272, 30314-30321). Characterization of the protein revealed that it is found in both the nucleus and cytoplasm and is highly expressed in cells that also express the integrin beta 4 subunit (Biffo et al.,
J. Biol. Chem.,
1997, 272, 30314-30321).
Integrin beta 4 binding protein has since been isolated by others under the names eIF6 and eIF3A, and has been shown to have a plurality of functions including ribosomal subunit assembly and stability as well as nuclear-cytoplasmic transport (Sanvito et al.,
J. Cell. Biol.,
1999, 144, 823-837; Si et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1997, 94, 14285-14290). The gene has been localized to human chromosome 20q11 and, because of its interactions with the integrin beta 4 subunit, is considered a candidate gene for a group of heritable diseases known as epidermolysis bullosa (EB)(Sanvito et al.,
Genomics,
1998, 52, 111-112).
In the mouse, integrin beta 4 binding protein, known as imc415, has additionally been shown to be involved in allergic inflammation, where it is thought to enhance protein synthesis (Cho et al.,
Biochem. Biophys. Res. Commun.,
1998, 252, 123-127; Wood et al.,
J. Biol. Chem.,
1999, 274, 11653-11659).
Integrin beta 4 binding protein has been shown to be overexpressed in colorectal neoplasms and carcinomas and this overexpression is thought to be an early event in the transition from benign to malignant colorectal phenotypes (Sanvito et al.,
Cancer Res.,
2000, 60, 510-516). For this reason the pharmacological modulation of integrin beta 4 binding protein activity and/or expression is believed to be an appropriate point of therapeutic intervention in pathological conditions involving aberrant or deregulated cell proliferation.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of integrin beta 4 binding protein and to date, strategies aimed at investigating integrin beta 4 binding protein function have involved the use of antibodies. Consequently, there remains a long felt need for agents capable of effectively inhibiting integrin beta 4 binding protein 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 integrin beta 4 binding protein expression.
The present invention provides compositions and methods for modulating integrin beta 4 binding protein expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding Integrin beta 4 binding protein, and which modulate the expression of Integrin beta 4 binding protein. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Integrin beta 4 binding protein 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 Integrin beta 4 binding protein 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 Integrin beta 4 binding protein, ultimately modulating the amount of Integrin beta 4 binding protein produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Integrin beta 4 binding protein. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Integrin beta 4 binding protein” encompass DNA encoding Integrin beta 4 binding protein, 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 Integrin beta 4 binding protein. 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 pro
Bennett C. Frank
Freier Susan M.
ISIS Pharmaceuticals Inc.
Lacourciere Karen A.
Licata & Tyrrell P.C.
McGarry Sean
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