Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-30
2003-07-29
Cochrane Carlson, Karen (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S300000, C530S399000, C435S007100, C435S069100, C435S440000
Reexamination Certificate
active
06599876
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a medicament useful for treating renal disease and to a method for treating renal disease by administration of such a medicament.
2. Description of the Related Art
Follistatin, a protein having the ability of binding to activin, has been discovered with reference to the activity of cultured pituitary gland cells to promote the production of follicle stimulating hormone (FSH) (Esch, F. S. et al.,
Mol. Endocrinol.;
1(11): 849-55 (1987). In the early stage of the study, it was found that follistatin inhibited the secretion of FSH. This suggested that follistatin will have a reverse activity with respect to activin, which promotes the secretion of FSH. Subsequent studies revealed that follistatin is a specific binding protein for activin that specifically binds to activin and inhibits its activity (Nakamura, T. et al.,
Science,
247 (4944): 836-08; (1990)). Several kinds of activin such as activin homdimer &bgr;A&bgr;A, activin heterodimer &bgr;A&bgr;B, activin homdimer &bgr;B&bgr;B, and the like occur in organisms, and follistatin is known to have inhibitory activity to any one of these activins (Fukui, A. et al.,
Dev. Biol.,
159(1): 131-139 (1993), Sugino, H. et al.,
Seikagaku,
68(8): 1405-1428 (1996)).
As a result of further studies on follistatin, the gene encoding it has been isolated and its amino acid sequence has also been reported (WO89/01945, Shimasaki, S., et al.,
Proc. Natl. Acad. Sci. USA,
85(12): 4218-22 (1988)).
Follistatin is known to have a pharmacological effect of promoting the cell growth of liver upon its topical administration (Kogure, K. et al.,
Hepatology,
24(2): 361-6 (1996), Kojima, I.,
BIO Clonica,
883(12), 43-46 (1997)). Also, it is reported that an antagonist of follistatin promotes cure of wounds and fibrous disorders with less cicatrization (WO97/15321). However, it has not yet been known that follistatin is effective in the therapy of renal diseases.
Heretofore, steroid preparations, prostaglandin preparations, hypotensive diuretic preparations and the like have been used as the medicament for treating renal diseases. However, the known medicaments are insufficient for radical cure.
DETAILED DESCRIPTION OF THE INVENTION
An object of the present invention is to provide a medicament for treating a renal disease that has different activity from that of conventional medicaments for treating renal diseases and enables effective treatment.
Another object of the present invention is to provide a method for treating a renal disease using such a medicament for treating a renal disease.
The present inventors have made extensive study with a view to solving the aforementioned problems, and as a result they have found that the expression of follistatin decreases in kidney having a disease. Also, paying attention to activin that presumably is associated with the growth of kidney cells and the function thereof, they have demonstrated by use of follistatin that inhibition of the activity of activin enables promotion of the proliferation of kidney cells. The present invention is thus completed based on this finding.
That is, the present invention provides a medicament for treating a renal disease, comprising a therapeutically effective amount of an activin inhibitor as an active ingredient.
Further the present invention provides the medicament used in treating renal disease with which activin activity is associated.
Further the present invention provides the medication where the activin inhibitor may be follistatin.
Further the present invention provides a method for treating a renal disease, comprising administering an activin inhibitor to a patient suffering from renal disease.
The biological reaction observed as the phenomenon of regeneration of tissue, that is, reconstruction of tissue is highly homologous with the phenomena such as differentiation, proliferation or migration of cells in organogenesis in the process of development and a common fluid factor may participate in both mechanisms.
Some growth factors in the organogenesis of kidney, whose representative examples include a hepatic cell growth factor (HGF) that is an indispensable differentiation inducing factor, reportedly promote each the proliferation of or inhibits apoptosis of uriniferous tubule cells in the regeneration of uriniferous tubule in kidney, that is regeneration of uriniferous tubule epithelium in various acute renal failure models (e.g., ischemia, nephrotoxic substances, etc.) to alleviate the renal functional disorder. As a result of studies thus far made, it can be anticipated that activin and follistatin are important differentiation inducing factors in the process of development of kidney and at the same time play a certain role in the phenomenon of regeneration based organ culture using a renal primordium, an in vitro model of lumen formation using MDCK cells (kidney from a female cocker spaniel, or phenotype of a transgenic mouse (Maeshima, A. et al.,
Biochem. Biophys. Res. Commun.,
268(2):445-9 (2000)). On the other hand, further studies are being progressed to elucidate that the role of activin and follistatin is a control mechanism of the initiation and termination of liver regeneration subsequent to hepatectomy of the liver (Kogure, K. et al.,
Hepatology,
24(2): 361-6 (1996), Kojima, I.,
b BIO Clonica,
883(12), 43-46 (1997)). Hence, the present inventors have made further study on the role of activin and follistatin in the regeneration of uriniferous tubule in kidney using an ischemic acute renal failure model.
The results of the above study suggest that changes in the expression of activin and follistatin observed after the ischemia/reperfusion of the liver will play some role in the regeneration of uriniferous tubule, as will be apparent from the examples described hereinbelow. That is, 48 hours after the ischemia/reperfusion, the expression of activin is exalted while the expression of follistatin, an antagonist against activin, is decreased. This suggests that activin is functionally in an activated state even temporarily. At present, it is unclear as to what significance such changes in the expressions of activin and follistatin will have in the regeneration of uriniferous tubule. However, in the studies on other organs thus far made, that is, regeneration phenomena in a brain ischemia model and a skin repairing model, it has been observed that the expression of activin is induced, and activin participates in the production of extracellular matrix and fibrosis of tissues. This suggests that activin may possibly participate in the prolongation of tissue disorder in a similar mechanism to that observed in kidney.
Accordingly, the present inventors have made a further study as to what an influence is given to the degree of uriniferous tubule regeneration and tissue disorder by administering follistatin, an antagonist against activin, to inhibit the activity thereof, and they have elucidated that the administration of follistatin results in a significant increase in cell number.
The foregoing results suggests that activin and follistatin may be important differentiation inducing factors in the process of development and regeneration of kidney and may have some role in the onset mechanism of the following pathology.
(1) Onset Mechanism of Uriniferous Tubule/Interstitial Tissue
Since tubulointerstitial disorder has a stronger correlation with the prognosis of a renal function than a glomerulus disorder, recently studies on the onset mechanism of a tubulointerstitial disorder are being progressed. The causes of the disorder include an ischemia/reperfusion disorder, a postrenal disorder, a drug-induced disorder as well as secondary causes that occur subsequent to the glomerulus disorder. Factors for developing such disorders include invasion of cells into the interstitial tissue, fibrosis of interstitial tissue, transformation of uriniferous tubule/interstitial cells, and the like.
The uriniferous tubule, like an ovary, is one of the tissues that express follistatin in larg
Ajinomoto Co. Inc.
Carlson Karen Cochrane
Liu Samuel Wei
LandOfFree
Medicament and method for treating renal disease does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Medicament and method for treating renal disease, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Medicament and method for treating renal disease will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3050569