Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Reexamination Certificate
2001-12-04
2004-12-07
Shukla, Ram R. (Department: 1635)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
C435S006120, C435S091100, C435S091310, C536S023100, C536S024500
Reexamination Certificate
active
06828151
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of hematopoietic cell protein tyrosine kinase. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding hematopoietic cell protein tyrosine kinase. Such compounds have been shown to modulate the expression of hematopoietic cell protein tyrosine kinase.
BACKGROUND OF THE INVENTION
Cells in higher animals normally divide only when they are stimulated by growth factors produced by other cells and act by binding to receptor tyrosine kinases on dividing cells. Cancer cells proliferate excessively because, as a result of accumulated mutations, they are able to divide without stimulation from other cells and therefore are no longer subject to normal controls on cell proliferation. The mutated genes which lead to excessive proliferation were originally called oncogenes before their origin as normal genes was understood. The normal genes, from which they arise, are thus often referred to as proto-oncogenes.
The cellular src gene was the first molecularly-defined proto-oncogene and its product, Src, is now known to be the source of the first detected tyrosine phosphorylation event. Mutations in the src gene, captured in the genome of Rous sarcoma virus, gave rise to the prototype oncogene v-src. Since the first descriptions of the protein tyrosine kinase activity of v-Src, many other proto-oncogenes have been described (Brown and Cooper,
Biochim. Biophys. Acta.,
1996, 1287, 121-149).
Intracellular tyrosine kinases can now be divided into at least 8 subfamilies based on catalytic domain sequence similarity and the presence or absence of other functional domains. The members of the Src family in vertebrates include Src, Fyn, Yes, Fgr, Hck, Lck, Blk and Yrk (Brown and Cooper,
Biochim. Biophys. Acta.,
1996, 1287, 121-149).
Hematopoietic cell protein tyrosine kinase (also known as Hck and JTK9) was first cloned in 1987 (Quintrell et al.,
Mol. Cell Biol.,
1987, 7, 2267-2275; Ziegler et al.,
Mol. Cell Biol.,
1987, 7, 2276-2285) and later mapped to chromosome 20q11-q12. The hematopoietic cell protein tyrosine kinase gene has been shown to encode two isoforms, p59
Hck
and p61
Hck
which are derived from a single mRNA by alternative initiation of translation (Robbins et al.,
Mol. Cell Biol.,
1995, 15, 3507-3515).
Hematopoietic cell protein tyrosine kinase expression is highest in differentiated monocytic and granulocytic cells, suggesting that the protein might function in myeloid differentiation or activation (Lichtenberg et al.,
Oncogene,
1992, 7, 849-858). Taguchi et al. have demonstrated that hematopoietic cell protein tyrosine kinase and Lyn are the major Src-family protein tyrosine kinases expressed in precursor lymphoblastic leukemia cells, the cell type from which childhood leukemia arises most frequently (Taguchi et al.,
Exp. Hematol
. (N.Y.), 2000, 28, 55-64).
Cartledge et al. have recently generated monoclonal antibodies to murine hematopoietic cell protein tyrosine kinase for the purpose of pursuing investigations of the roles of hematopoietic cell protein tyrosine kinase in signal transduction (Cartledge et al.,
Hybridoma,
2000, 19, 323-330)
Hematopoietic cell protein tyrosine kinase has been demonstrated to interact with Bcr-Abl, a constitutively active protein tyrosine kinase expressed as a result of the Philadelphia translocation in chronic myelogenous leukemia. Kinase-defective hematopoietic cell protein tyrosine kinase was found to suppress Bcr-Abl-induced outgrowth of the cytokine-dependent myeloid leukemia cell line (Lionberger et al.,
J. Biol. Chem.,
2000, 275, 18581-18585).
Investigations of polymorphonuclear neutrophils isolated from mice deficient in hematopoietic cell protein tyrosine kinase and Fgr have identified a role for these Src family kinases in a signaling pathway leading to granule-plasma membrane fusion and have identified Fgr and hematopoietic cell protein tyrosine kinase as potential targets for pharmacological control of the inflammatory process (Mocsai et al.,
J. Immunol.,
1999, 162, 1120-1126).
Investigations of encephalomyocarditis virus-infected mice treated with the Src kinase inhibitor PP2 have indicated that hematopoietic cell protein tyrosine kinase plays an important role in the activation of macrophages and the subsequent production of tumor necrosis factor-alpha and nitric oxide which lead to the destruction of pancreatic beta cells, leading to diabetes. The inhibition of hematopoietic cell protein tyrosine kinase was found to prevent the onset of diabetes in this study (Choi et al.,
J. Virol.,
2001, 75, 1949-1957).
Hematopoietic cell protein tyrosine kinase and Fgr double knock-out mice have been found to be resistant to endotoxic shock and exhibit reduced neutrophil migration, indicating that hematopoietic cell protein tyrosine kinase may be an appropriate target for therapeutic intervention in inflammatory diseases (Lowell and Berton,
Proc. Natl. Acad. Sci. U.S.A.,
1998, 95, 7580-7584).
Tokunaga et al. have reported inhibition of human immunodeficiency virus type 1 (HIV-1) infectivity by the expression of a dominant-negative hematopoietic cell protein tyrosine kinase protein in T293 cells, indicating a role of Src kinases in regulation of entry of HIV-1 into target cells (Tokunaga et al.,
J. Virol.,
1998, 72, 6257-6259).
Small molecule inhibitors of Src family tyrosine kinases are well known in the art. Examples include natural products such as radiciol and geldanamycin, ring-fused pyrimidines, benzopyrans and thiol-reactive agents (Showalter and Kraker,
Pharmacol. Ther.,
1997, 76, 55-71).
Schindler et al. have reported the crystal structure of hematopoietic cell protein tyrosine kinase in complex with a pyrazolo pyrimidine-type Src family kinase inhibitor known as PP1 (Schindler et al.,
Mol. Cell,
1999, 3, 639-648).
A 21-mer antisense phosphorothioate oligonucleotide targeting the seven codons immediately downstream from the translation initiation site of the murine hematopoietic cell protein tyrosine kinase gene has been used to inhibit hematopoietic cell protein tyrosine kinase expression in investigations of tumor necrosis factor production by murine macrophages (English et al.,
J. Exp. Med.,
1993, 178, 1017-1022) and lipopolysaccharide and interferon-gamma-mediated phosphorylation of the proto-oncogene vav (English et al.,
J. Leukocyte Biol.,
1997, 62, 859-864).
A 20-mer phosphorothioate oligonucleotide targeting the start codon of human hematopoietic cell protein tyrosine kinase was used to inhibit hematopoietic cell protein tyrosine kinase in investigations of neutrophil apoptosis stimulated by granulocyte-macrophage colony-stimulating factor (Wei et al.,
J. Immunol.,
1996, 157, 5155-5162).
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of hematopoietic cell protein tyrosine kinase. To date, investigative strategies aimed at modulating hematopoietic cell protein tyrosine kinase expression have involved the use of antibodies, small molecule inhibitors and antisense oligonucleotides. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting hematopoietic cell protein tyrosine kinase 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 expression of hematopoietic cell protein tyrosine kinase.
The present invention provides compositions and methods for modulating expression of hematopoietic cell protein tyrosine kinase.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding hematopoietic cell protein tyrosine kinase, and which modulate the expression of hematopoietic cell protein tyrosine kinase. Pharmaceutical and other compositions comp
Borchers Alexander H.
Dobie Kenneth W.
ISIS Pharmaceuticals Inc.
Licata & Tyrrell P.C.
Shukla Ram R.
Zara Jane
LandOfFree
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