Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-14
2002-08-20
Wang, Andrew (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S091100, C435S091300, C435S325000, C435S375000, C536S023100, C536S023200, C536S024500, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06436909
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of transforming growth factor-&bgr; (TGF-&bgr;). In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human TGF-&bgr;. Such oligonucleotides have been shown to modulate the expression of TGF-&bgr;.
BACKGROUND OF THE INVENTION
Transforming growth factor-&bgr; (TGF-&bgr;) is a cytokine which regulates biological processes such as cell proliferation, differentiation and immune reaction. It has been found to have many actions in tissue repair, stimulating the deposition of extracellular matrix in multiple ways. TGF-&bgr; stimulates the synthesis of matrix proteins including fibronectin, collagens and proteoglycans. It also blocks the degradation of matrix by inhibiting protease secretion and by inducing the expression of protease inhibitors. It also facilitates cell-matrix adhesion and matrix deposition via modulation of expression of integrin matrix receptors, and lastly TGF-&bgr; also upregulates its own expression. TGF-&bgr; exists in three isoforms in mammals: TGF-&bgr;1, -2 and -3. These function similarly in vitro.
Fibrosis is a pathological process, usually resulting from injury, which can occur in any organ. Excessive amounts of extracellular matrix accumulate within a tissue, forming scar tissue which causes dysfunction and, potentially, organ failure. Fibrosis can be either chronic or acute. Chronic fibrosis includes fibrosis of the major organs, most commonly liver, kidney and/or heart, and normally has a genetic or idiopathic origin. Progressive fibrosis of the kidney is the main cause of chronic renal disease. In diabetics, fibrosis within glomeruli (glomerulosclerosis) and between tubules (tubulointerstitial fibrosis) causes the progressive loss of renal function that leds to end-stage renal disease. Fibrotic lung disorders include some 180 different conditions and result in severe impairment of lung function.
Acute fibrosis is associated with injury, often as a result of surgery. Surgical adhesion represents the largest class of acute fibrosis. Surgery often results in excessive scarring and fibrous adhesions. It is estimated that over 90% of post-surgical patients are affected by adhesions. Abdominal adhesions can lead to small bowel obstruction and female infertility. Fibrosis after neck and back surgery (laminectomy, discectomy) can cause significant pain. Fibrosis after eye surgery can impair vision. Pericardial adhesions after coronary bypass surgery, fibrosis after organ transplant rejection and general scarring after plastic surgery are other examples. This represents a major unmet medical need.
Antisense and other inhibitors of TGF-&bgr; have been used to elucidate the role of TGF-&bgr;s in cancer, anaphylaxis, fibrosis and other conditions. As examples:
Dzau (WO 94/26888) discloses use of antisense sequences which inhibit the expression of cyclins and growth factors including TGF-&bgr;
1
, TGF, bFGF, PDGF for inhibiting vascular cellular activity of cells associated with vascular lesion formation in mammals.
Shen et al. discloses use of phosphorothioate antisense oligonucleotides targeted to TGF-&bgr;2 to reduce TGF-&bgr;2 expression in U937 cells (Bioorg. Med. Chem. Lett., 1999, 9, 13-18).
Schuftan et al. (1999,
Eur. J. Clin Invest.,
29, 519-528) disclose use of a2-macroglobin or antisense to TGF-&bgr;1 to reduce extracellular matrix synthesis in cultured rat hepatic stellate cells.
Kim et al. have used antisense oligonucleotides targeted to TGF-&bgr;1 to inhibit passive cutaneous anaphylaxis and histamine release. 1999,
J. Immunol.
162, 4960-4965.
Kim et al. have also used an antisense TGF-&bgr;1 oligodeoxynucleotide to inhibit wound-induced expression of TGF-&bgr;1 mRNA in mouse skin. Pharmacol. Res., 1998, 37, 289-293.
Liu et al. used TGF-&bgr; antibody or antisense to TGF-&bgr;1 to inhibit secretion of plasminogen activator inhibitor-1 in EGR-1 regulated cells. 1999,
J. Biol. Chem.
274, 4400-4411. Arteaga et al. used antibodies or antisense oligonucleotides targeted to TGF-&bgr;2 to enhance sensitivity of cancer cells to NK cells in the presence of tamoxifen. 1999,
J. Nat. Cancer Inst.
91, 46-53.
Tzai et al., 1998,
Anticancer Res.,
18, 1585-1589, used antisense oligonucleotides specific for TGF-&bgr;1 to inhibit in vitro and in vivo growth of murine bladder cancer cells.
The role of TGF-&bgr; in diabetic nephropathy is reviewed in Hoffman, et al., 1998, Electrolyte Metab., 24, 190-196.
Neutralizing anti-TGF-&bgr; antibodies or antisense oligonucleotides directed to TGF-&bgr;1 are reported to prevent the hypertrophic effects of high glucose and the stimulation of matrix synthesis in renal cells.
Antisense phosphorothioate oligodeoxynucleotides targeted to TGF-&bgr;3 were used by Nakajima et al. (1998, Japan. Dev. Biol, 194, 99-113; abstract only) and others to block transformation of atrioventricular canal endothelial cells into invasive mesenchyme.
Chung et al. (U.S. Pat. No. 5,683,988) disclose and claim particular antisense oligodeoxynucleotides targeted to TGF-&bgr; and use of these to inhibit scarring.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding TGF-&bgr;, and which modulate the expression of TGF-&bgr;. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of TGF-&bgr; 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 TGF-&bgr; 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 antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding TGF-&bgr;, ultimately modulating the amount of TGF-&bgr; produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding TGF-&bgr;. As used herein, the terms “target nucleic acid” and “nucleic acid encoding TGF-&bgr;” encompass DNA encoding TGF-&bgr;, 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 TGF-&bgr;. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene product. In the context of the present invention, inhibition is a preferred form of modulation of gene expression and mRNA is a preferred target. Further, since many genes (including TGF-&bgr;) have multiple transcripts, “modulation” also includes an alteration in the ratio between gene products, such as alteration of mRNA splice products.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular n
Dean Nicholas M.
Murray Susan F.
ISIS Pharmaceuticals Inc.
Lacourciere Karen
Licata & Tyrrell P.C.
Wang Andrew
LandOfFree
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