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Title:  Composition for improving pancreatic function

United States Patent:  6,232,288

Inventors:  Kojima; Itaru (Maebashi, JP)

Assignee:  Takeda Chemical Industries, Ltd. (Osaka, JP)

Appl. No.:  051624

Filed:  April 15, 1998

PCT Filed:  November 8, 1996

PCT NO:  PCT/JP96/03277

371 Date:  April 15, 1998

102(e) Date:  April 15, 1998

PCT PUB.NO.:  WO97/17086

PCT PUB. Date:  May 15, 1997

Foreign Application Priority Data:  Nov 09, 1995[JP] (7-291238)


Abstract

The present invention provides a novel composition comprising a betacellulin protein, or a fragment thereof, which is capable of promoting the differentiation of undifferentiated pancreatic cells into insulin-producing beta cells or pancreatic polypeptide producing F cells. This composition can also improve glucose tolerance in patients and inhibit the growth of undifferentiated pancreatic cells. The composition may further comprise activin and/or other molecules. Methods for treating mammals, including humans, are also provided.

DISCLOSURE OF THE INVENTION

Diabetes mellitus is a disease characterized by the onset of various complications associated with persistent hyperglycemia. This disease is classified into insulin-dependent, insulin-independent and other types, and is thought to be associated with diverse causes, but basically it develops when insulin action is diminished. Insulin-dependent diabetes mellitus, in particular, is caused by an absolute lack of insulin production. Against this background is there a need for the development of a medicine which improves pancreatic function to prevent or treat diabetes mellitus etc.

In view of the above problems, the present inventors made extensive investigation and found that known BTC protein acts on cells derived from the pars exocrina pancreatis capable of multiple differentiation to allow them to differentiate to beta cells etc. The present inventors made further investigation based on this finding, and developed the present invention.

Accordingly, the present invention provides:

(1) A composition for improving pancreatic function which comprises a betacellulin protein or a mutein thereof;

(2) The composition according to (1), wherein the betacellulin protein is a protein having the amino acid sequence shown by at least one SQ ID NO. selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;

(3) The composition according to (1), wherein the betacellulin protein is a protein having the amino acid sequence shown by SEQ ID NO:1 or a protein having the amino acid sequence shown by SEQ ID NO:2;

(4) The composition according to (1), wherein the mutein of the betacellulin protein is a protein having (i) an amino acid sequence resulting from deletion of about 1 to 40 amino acids from the amino acid sequence shown by SEQ ID NO:1 or SEQ ID NO:2, (ii) an amino acid sequence resulting from replacement of about 1 to 40 amino acids in the amino acid sequence shown by SEQ ID NO:1 or SEQ ID NO:2 by other amino acid sequences, or (iii) an amino acid sequence resulting from addition of about 1 to 40 amino acids to the amino acid sequence shown by SEQ ID NO:1 or SEQ NO:2;

(5) The composition according to (1), wherein the mutein of the betacellulin protein is a protein having an amino acid sequence resulting from deletion of 12 or 30 amino acids from the N-terminus of the amino acid sequence shown by SEQ ID NO:1;

(6) The composition according to (1) to (5), which further contains an activin;

(7) The composition according to (6), wherein the content ratio of the activin to the betacellulin protein or a mutein thereof is about 1:10 to 10:1;

(8) The composition according to (1) to (7), which is a composition for preventing or treating diabetes mellitus.

(9) The composition according to (1) to (7), which is a composition for preventing or treating pancreatic dysfunction in diabetes mellitus or pancreatic hypofunction associated with senile insulin secretion reduction;

(10) A composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells, which comprises a betacellulin protein or a mutein thereof;

(11) A composition for preventing or treating undifferentiated type of pancreatic cancer, which comprises a betacellulin protein or a mutein thereof;

(12) A method for improving pancreatic function of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;

(13) A method for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;

(14) A method for preventing or treating undifferentiated type of pancreatic cancer of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;

(15) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for improving pancreatic function;

(16) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells;

(17) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for preventing or treating undifferentiated pancreatic cancer.

Also, the present invention further provides:

(18) A composition for improving pancreatic function which comprises a DNA coding for a betacellulin protein or a mutein thereof;

(19) A composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells, which comprises a DNA coding for a betacellulin protein or a mutein thereof;

(20) A composition for preventing or treating undifferentiated pancreatic cancer, which comprises a DNA coding for a betacellulin protein or a mutein thereof;

(21) A method for improving pancreatic function of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;

(22) A method for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;

(23) A method for preventing or treating undifferentiated pancreatic cancer;

(24) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for improving pancreatic function;

(25) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells; and

(26) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for preventing or treating undifferentiated type of pancreatic cancer.

Claim 1 of 26 Claims

What is claimed is:

1. A method for treating a mammal comprising administering to said mammal an effective amount of a composition comprising a betacellulin protein wherein said betacellulin protein comprises the amino acid sequence of SEQ ID NO: 1, the amino acid sequence of SEQ ID NO: 2, or a fragment of either of the amino acid sequences of SEQ ID NOs: 1 or 2, and a pharmaceutically acceptable carrier, wherein said betacellulin protein has the activity of

a) promoting the differentiation of undifferentiated pancreatic cells to insulin-producing beta cells;

b) promoting the differentiation of undifferentiated pancreatic cells to pancreatic polypeptide producing F cells;

c) improving glucose tolerance in a patient suffering from below normal insulin activity;

d) improving glucose tolerance in a patient suffering from insulin-dependent diabetes mellitus; or

e) inhibiting the growth of undifferentiated pancreatic cancer cells.

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