Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-04-11
1999-01-12
Ulm, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514866, 530399, C07K 14475, A61K 3818
Patent
active
058589775
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the application of keratinocyte growth factor to treat or prevent the onset of diabetes mellitus.
BACKGROUND OF THE INVENTION
Keratinocyte growth factor (KGF) is a growth factor specific for epithelial cells that was first identified in conditioned medium of a human embryonic lung fibroblast cell line. Rubin et al., Proc. Natl. Acad. Sci. USA 86:802-806 (1989). Expression of messenger RNA for KGF has been detected in several stromal fibroblast cell lines derived from epithelial tissues at various stages of development. The transcript for KGF was also evident in RNA extracted from normal adult kidney and organs of the gastrointestinal tract. Finch et al., Science 245:752-755 (1989). Evidence that KGF is secreted from fibroblasts in culture and is expressed in vivo in the dermis but not epidermis indicates that KGF may be an important normal paracrine effector of keratinocyte proliferation. Studies have shown that KGF is as potent as EGF in stimulating the proliferation of primary or secondary human keratinocytes in tissue culture. Marchese et al., J. Cell. Phys. 144:326-332 (1990).
Ex vivo and in vivo studies in normal adult animals have shown that KGF produces changes in hair follicle morphogenesis, hepatocyte proliferation, and epithelial cell proliferation in the lung, breast, pancreas, stomach, small intestine, and large intestine. Panos et al., J. Clin. Invest. 92:969-977 (1993); Ulich et al., Am. J. Path. 144:862-868 (1994); Yi et al., Am. J. Path. 145:80-85 (1994); and Ulich et al., J. Clin. Invest. 93:1298-1306 (1994). The role of KGF in embryonic or neonatal development has not been studied in detail; however, KGF has been documented to be an important mediator of seminal vesicle development in the newborn mouse. Alarid et al., P.N.A.S. 91:1074-1078 (1994).
Published PCT patent application WO 90/08771 describes the purification of KGF from the conditioned medium of a human embryonic fibroblast cell line, the partial amino acid sequencing of purified KGF, the cloning of the gene, and the expression of the gene in bacterial cells to yield biologically active recombinant KGF. The aforementioned publication discloses that KGF or KGF-like polypeptides can be used as wound healing agents for burn wounds or to stimulate transplanted corneal tissue. In fact, KGF has been demonstrated to increase re-epithelialization and increased thickness of the epithelium when recombinant KGF was topically applied to wounds surgically induced in the rabbit ear or in porcine skin. Pierce et al., J. Exp. Med. 179:831-840 (1994); and Staiano-Coico et al., J. Exp. Med. 178:865-878 (1993).
SUMMARY OF THE INVENTION
The discovery has now been made that KGF is useful to treat the medical disorder known as diabetes.
FIG. 1 is a bar graph depicting the effects of KGF in rats following daily subcutaneous administration at a dose of 5 milligrams per kilogram of body weight (mg/kg) over seven days. Streptozotocin (55 mg/kg) was administered once intravenously two days after the initiation of KGF treatment. The KGF-treated group of diabetic rats is shown in the right half of the figure, above the legend "Strep+KGF". Control groups are represented to the left and right of that: treatment over seven days with sodium chloride solution and no diabetes induction ("NaC1"), treatment over seven days with sodium chloride solution before and after streptozotocin-induced diabetes ("Strep"), and treatment over seven days with KGF and no diabetes induction ("KGF"). Non-fasting blood glucose levels in milligrams per deciliter (mg/dl) are shown on the vertical axis, as measured on the fifth day after diabetes induction (i.e., seventh day after KGF or sodium chloride treatment was initiated). There were four rats per group.
FIG. 2 is a bar graph depicting the effect of KGF in the same rat model on other physiological measurements relating to diabetes. Fasting urine glucose levels in mg/dl and fasting urine output in milliliter (ml) excreted in twenty four hours on the seventh day of KGF
REFERENCES:
patent: 5626617 (1997-05-01), Brewitt
Aukerman Sharon Lea
Pierce Glenn Francis
Amgen Inc.
Mazza Richard J.
Odre Steven M.
Saoud Christine
Ulm John
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