Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-10-09
2004-06-15
Shukla, Ram R. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S458000, C536S023100, C536S024500
Reexamination Certificate
active
06750019
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of insulin-like growth factor binding protein 5. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding insulin-like growth factor binding protein 5. Such compounds have been shown to modulate the expression of insulin-like growth factor binding protein 5.
BACKGROUND OF THE INVENTION
The insulin-like growth factor (IGF) family includes insulin-like growth factors type I and II (IGF-I and IGF-II) which are structurally related to pro-insulin. IGFs act as potent mitogens to regulate somatic growth, cellular proliferation, and cellular differentiation. Their action is determined by the availability of free IGFs to interact with IGF receptors. The level of free IGFs in a cell is modulated by the rate of IGF production and clearance, and also by their interaction with insulin-like growth factor binding proteins (IGFBPs) and IGFBP-related proteins (IGFBP-rPs) (Wetterau et al.,
Mol. Genet. Metab.,
1999, 68, 161-181).
The superfamily of insulin-like growth factor binding proteins comprises six IGFBPs that bind to IGFs with high affinity, and an emerging group of nine IGFBP-related proteins which bind to IGFs with lower affinity. Cleavage of IGFBPs by proteases also modulates the levels and the action of free IGFs and IGFBPs. IGFBPs not only regulate IGF action and bioavailability, but also appear to mediate IGF-independent actions including inhibition or enhancement of cell growth and induction of apoptosis. The growth inhibitory effects of sequestration by IGFBPs are evidenced when they competitively bind IGFs and modulate their interactions with type I IGF cell surface receptors (Wetterau et al.,
Mol. Genet. Metab.,
1999, 68, 161-181).
Using the amino terminal sequence of the purified rat insulin-like growth factor binding protein 5 (also known as insulin-like growth factor binding protein 5 precursor, IGF-binding protein 5, IGFBP5, igfbp-5, and IBP5) to prepare degenerate oligonucleotide probes, the rat and human genes were cloned from rat ovary and human placental cDNA libraries (Shimasaki et al.,
J. Biol. Chem.,
1991, 266, 10646-10653). The human genes for insulin-like growth factor binding protein 5 and insulin-like growth factor binding protein 2 are physically linked, as are the homologous mouse genes, which colocalize on mouse chromosome 1 in a region of synteny with the human chromosomal locus 2q33-q36 (Kou et al.,
Genomics,
1994, 21, 653-655). The human gene was mapped to chromosome 2 using a panel of somatic cell hybrids, and by fluorescence in situ hybridization to the 2q33-q34 locus (Allander et al.,
J. Biol. Chem.,
1994, 269, 10891-10898).
Disclosed and claimed in the PCT publications WO 92/03470 and WO 92/03471 are recombinant DNA molecules encoding insulin-like growth factor binding protein 5 and subsequences thereof, microorganisms and cell lines containing said molecules, methods for preparing insulin-like growth factor binding protein 5 from these, and the purified protein itself, as well as antibodies to the protein and derivatives thereof (Kiefer and Masiarz, 1992; Kiefer et al., 1992).
Fetal tissues express high levels of insulin-like growth factor binding protein 5 during rapid growth, but tissue levels vary in adults. Insulin-like growth factor binding protein 5 is the main IGFBP expressed in the kidney and it is found in substantial amounts in connective tissues and cerebrospinal fluid. Serum levels of insulin-like growth factor binding protein 5 also decrease with age, starting after puberty. Levels in older women are 30% of those of teenagers (Wetterau et al.,
Mol. Genet. Metab.,
1999, 68, 161-181).
Insulin-like growth factor binding protein 5 has several unique features that suggest it is a key component of the IGF system in bone. Bone cells produce large amounts of insulin-like growth factor binding protein 5, but levels decrease during maturation due to protease activity. Unlike other IGFBPs, insulin-like growth factor binding protein 5 has a high specific binding affinity for hydroxyapatite and extracellular matrix proteins, and thus it is stored in abundance within bone. It appears to act as a growth factor, stimulating bone formation via a mechanism independent of IGF-I, an effect specific for insulin-like growth factor binding protein 5 and not other IGFBPs. It is the only IGFBP shown to stimulate osteoblast cell proliferation in vitro. A single local injection of insulin-like growth factor binding protein 5 into the outer periosteum of the parietal bone of IGF-I knockout mice increased alkaline phosphatase and osteocalcin levels of calvarial bone extracts. A significant age-related decrease in insulin-like growth factor binding protein 5 could contribute in part to the age-related impairment in the coupling of bone formation to resorption (Miyakoshi et al.,
J. Clin. Invest.,
2001, 107, 73-81).
Insulin-like growth factor binding protein 5 is a component of a ternary complex in human serum. The other two components of this complex are an insulin-like growth factor and a glycoprotein known as the acid labile subunit (ALS). Formation of this ternary complex stabilizes insulin-like growth factor binding protein 5 levels and is hypothesized to provide a circulating reservoir of insulin-like growth factor binding protein 5 and IGFs, implying a previously unrecognized form of IGF transport and delivery in the circulation and a novel mechanism for regulating its bioavailability (Twigg and Baxter,
J. Biol. Chem.,
1998, 273, 6074-6079). A basic carboxyl-terminal domain of the protein is the principal site in insulin-like growth factor binding protein 5 responsible for ALS binding (Twigg et al.,
J. Biol. Chem.,
1998, 273, 28791-28798).
Specific antisera against insulin-like growth factor binding protein 5 have been generated. Mouse embryos as well as tissues from mice with a targeted disruption of insulin-like growth factor binding protein 5 were used to confirm histochemically that insulin-like growth factor binding protein 5 is expressed in various tissues such as kidney, liver, endothelium of the gut, tubules and mesenchyme of the lung, meninges, notochord, muscle and tongue. Differences between mRNA and protein localization suggest that the protein is secreted and transported (van Kleffens et al.,
Endocrinology,
1999, 140, 5944-5952).
Levels of insulin-like growth factor binding protein 5 mRNA are increased in inflamed colon smooth muscle cells in an experimental model of colitis in rat (Zeeh et al.,
J. Recept. Signal Transduct. Res.,
1998, 18, 265-280).
Insulin-like growth factor binding protein 5 has also been implicated in prostate cancer progression (Miyake et al.,
Cancer Res.,
2000, 60, 3058-3064), is expressed with high frequency in neuroendocrine tumors (Wulbrand et al.,
Eur. J. Clin. Invest.,
2000, 30, 729-739), and has been shown to be induced upon treatment of breast cancer cells with antiestrogens used to abolish tamoxifen resistant proliferation (Huynh et al.,
Cell Growth Differ.,
1996, 7, 1501-1506; Parisot et al., Breast Cancer Res. Treat., 1999, 55, 231-242).
The pharmacological modulation of insulin-like growth factor binding protein 5 activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in developmental or growth disorders, and in pathological conditions such as cancer, colitis, Duchenne muscular dystrophy, diabetes and other metabolic diseases, such as osteoporosis and osteopetrosis.
Antisense mediated inhibition of insulin-like growth factor binding protein 5 has been utilized as an investigative tool to elucidate its mitogenic action in IGF signal transduction pathways and as a therapeutic agent for prostate cancer progression in a mouse model (Miyake et al.,
Cancer Res.,
2000, 60, 3058-3064).
A phosphorothioate antisense oligonucleotide, 18 nucleotides in length and complementary to the translation initiation site of the mouse insulin-like growth factor binding protein
ISIS Pharmaceuticals Inc.
Licata & Tyrrell P.C.
Shukla Ram R.
Zara Jane
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