Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-09-13
2004-03-23
Lacourciere, Karen (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06710174
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of vascular endothelial growth factor receptor-1. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding vascular endothelial growth factor receptor-1. Such compounds have been shown to modulate the expression of vascular endothelial growth factor receptor-1.
BACKGROUND OF THE INVENTION
As a mitogen that acts primarily on endothelial cells, vascular endothelial growth factor (VEGF, or VEGF-A) is essential for endothelial cell differentiation (vasculogenesis) and for the sprouting of new capillaries from pre-existing vessels (angiogenesis) during embryonic development and wound repair. Signaling by VEGF affects a number of biological functions, including endothelial cell survival via inhibition of apoptosis, cell proliferation, vascular permeability, monocyte activation, chemotaxis, and cell migration. Thus, VEGF is believed to play a key role in wound healing, postnatal angiogenesis during pregnancy, and in human pathophysiological conditions such as cancer, rheumatoid arthritis, ocular neovascular disorders, and cardiovascular disease (Zachary and Gliki,
Cardiovasc. Res.,
2001, 49, 568-581).
For transmission of the VEGF signal, VEGF binds to three receptor protein tyrosine kinases, vascular endothelial growth factor receptors-1, -2, and -3, that are structurally related to the PDGF family of class III receptors, characterized by cytoplasmic regions with an insert sequence within the catalytic domain, a single transmembrane domain, and seven immunoglobulin-like extracellular domains. Monomeric vascular endothelial growth factor receptors have 100-fold less affinity for VEGF, and thus, ligands preferentially bind to predimerized receptors. Upon ligand binding, the receptors auto- or trans-phosphorylate specific cytoplasmic tyrosine residues to initiate an intracellular cascade of signaling that ultimately reaches nuclear transcription factor effectors (Zachary and Gliki,
Cardiovasc. Res.,
2001, 49, 568-581).
Most biological functions of VEGF are mediated through vascular endothelial growth factor receptor-2, and the role of vascular endothelial growth factor receptor-1 is currently less well understood (Zachary and Gliki,
Cardiovasc. Res.,
2001, 49, 568-581).
Vascular endothelial growth factor receptor-1 (also known as VEGF receptor-1, VEGFR1, fms-related tyrosine kinase 1, Flt-1, FLT1, oncogene flt, and vascular endothelial growth factor/vascular permeability factor receptor) binds VEGF with highest affinity, but also binds VEGF-B (an alternative splice form of VEGF), and the closely related placenta growth factor (PlGF) with weaker affinities (Shibuya,
Int. J. Biochem. Cell Biol.,
2001, 33, 409-420).
The human vascular endothelial growth factor receptor-1 gene was originally isolated from a human placenta DNA library (Shibuya et al.,
Oncogene,
1990, 5, 519-524) and its physical map location was confirmed when a yeast artificial chromosome (YAC) from human chromosomal band 13q12, bearing the closely linked FLT1 and FLT3 genes, was isolated and characterized (Imbert et al.,
Cytogenet. Cell. Genet.,
1994, 67, 175-177).
Expression of VEGF receptor-1 was once believed to restricted to proliferating endothelial cells, but expression of both VEGF receptor-1 and VEGF receptor-2 has been demonstrated more recently in atherosclerotic lesions and in several non-endothelial tumor cell types (Epstein et al.,
Cardiovasc. Res.,
2001, 49, 532-542). For example, co-expression of both receptors with VEGF is found in melanoma cells derived from primary and metastatic lesions (Graeven et al.,
J. Cancer Res. Clin. Oncol.,
1999, 125, 621-629).
Vascular endothelial growth factor receptor-1 was also found to be expressed in human peripheral blood monocytes and stimulates tissue factor production and chemotaxis, mediating monocyte recruitment and procoagulant activity (Clauss et al.,
J. Biol. Chem.,
1996, 271, 17629-17634). Expression of both VEGF-B and vascular endothelial growth factor receptor-1 is significantly upregulated renal clear cell carcinomas (Gunningham et al.,
Cancer Res.,
2001, 61, 3206-3211), and expression of vascular endothelial growth factor receptor-1 is also significantly higher in breast carcinoma as compared to normal breast (Gunningham et al.,
J. Pathol.,
2001, 193, 325-332).
Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection, developing in nearly 30% of all cases. Characteristics of these KS tumors are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. Vascular endothelial growth factor receptor-1 is expressed at high levels in AIDS-KS cell lines, while normal skin cells from the same patients did not express vascular endothelial growth factor receptor-1, suggesting that vascular endothelial growth factor receptor-1 plays a role in the development and progression of KS (Masood et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1997, 94, 979-984).
Domain deletion studies of vascular endothelial growth factor receptor-1 have been performed, and it was determined that only two of the immunoglobulin-like extracellular domains of vascular endothelial growth factor receptor-1 are necessary and sufficient for binding VEGF with near-native affinity. The crystal structure of a complex between domain 2 of vascular endothelial growth factor receptor-1 and VEGF has been determined at 1.7-angstrom resolution (Wiesmann et al.,
Cell,
1997, 91, 695-704).
Vascular endothelial growth factor receptor-1 has a dual function in angiogenesis, acting as a positive or negative regulatory factor in different biological conditions. Under pathological conditions, such as when tumor-forming murine Lewis lung carcinoma (LLC) cells overexpressing placenta growth factor-2 (a ligand specific for vascular endothelial growth factor receptor-1) are injected into mice, vascular endothelial growth factor receptor-1 acts as a positive signal transducer and angiogenesis is induced, stimulating tumor growth. When the same LLC cells are overexpressing VEGF and are injected into mice, there is no increase in tumor growth rate (Hiratsuka et al.,
Cancer Res.,
2001, 61, 1207-1213).
Vascular endothelial growth factor receptor-1 can also act as a negative regulator of vascular endothelial growth factor receptor-2. Differential splicing of the vascular endothelial growth factor receptor-1 transcript results in a full-length receptor and a naturally occurring, soluble form of the extracellular domain of vascular endothelial growth factor receptor-1 (sVEGFR-1 or sFLT-1). This sFLT-1 isoform can form heterodimers with vascular endothelial growth factor receptor-2 (Kendall et al.,
Biochem. Biophys. Res. Commun.,
1996, 226, 324-328), and when overexpressed, sFLT-1 but not an artificial, soluble vascular endothelial growth factor receptor-2, can act as a receptor antagonist and inhibit VEGF-induced cell proliferation and migration of human microvascular endothelial cells and human umbilical vein endothelial cells (HUVECs) by forming and inactive complex with VEGF and with full length vascular endothelial growth factor receptor-2 (Roeckl et al.,
Exp. Cell Res.,
1998, 241, 161-170; Zachary and Gliki,
Cardiovasc. Res.,
2001, 49, 568-581). By influencing the availability of VEGF and placental growth factor-2, sFLT-1 acts as an antagonist to VEGF action and is believed to play a pivotal role in generation of placental vascular diseases like pre-eclampsia or intrauterine growth retardation (Hornig et al.,
Lab. Invest.,
2000, 80, 443-454).
Because sFLT-1 has a strong affinity for VEGF, it has also been tested as a VEGF-blocking reagent in experimental animal models for carcinogenesis and shown to be effective in the suppression of solid tumor growth (Goldman et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1998, 95, 8795-8800).
Disclosed and claimed in U.S. Pat. No. 5,861,484 are naturally occurring or recombinantly engineered soluble VEGF receptor-related inhibit
Bennett C. Frank
Watt Andrew T.
ISIS Pharmaceuticals Inc.
Lacourciere Karen
Licata & Tyrrell P.C.
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