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TGF-Alpha POLYPEPTIDES, FUNCTIONAL FRAGMENTS AND METHODS OF USE THEREFOR

a technology of transforming growth factor alpha and polypeptide, applied in the field of tissue repair, can solve the problems of destroying healthy cells, affecting the subject being treated, and patients receiving total parenteral nutrition, and achieve the effect of expanding the population of insulin-producing cells and expanding the population of subjects

Inactive Publication Date: 2008-10-02
TWARDZIK DANIEL R +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]In another embodiment, the present invention provides a method for treating Type I or Type II diabetes by expanding a subject's population of insulin-producing cells. The method includes administering an effective amount of a TGF-α polypeptide (SEQ ID NO:1), a TGF-α related polypeptide, a TGF-α57 polypeptide (SEQ ID NO:3), a fragment thereof, or a mimetic thereof in an amount effective to expand the population of insulin-producing cells.
[0017]Also provided is a method for treating AIDS and HIV infection by increasing a subject's population of CD4+ T cells. The method includes administering an effective amount of a TGF-α polypeptide (SEQ ID NO:1), a TGF-α related polypeptide, a TGF-α57 polypeptide (SEQ ID NO:3), a fragment thereof, or a mimetic thereof.

Problems solved by technology

For example, in some instances, a particular treatment for a disease often detrimentally affects the subject being treated.
One such example, is the administration of chemotherapeutic agents to subjects, which results in destruction of healthy cells, for example, cells of the gastrointestinal tract.
The pain associated with oral mucositis may be severe requiring narcotic analgesics, and the difficulty in eating can result in patients receiving total parenteral nutrition.

Method used

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  • TGF-Alpha POLYPEPTIDES, FUNCTIONAL FRAGMENTS AND METHODS OF USE THEREFOR
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  • TGF-Alpha POLYPEPTIDES, FUNCTIONAL FRAGMENTS AND METHODS OF USE THEREFOR

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0153]Each of the three loop regions in human TGFα was investigated for TGFα-like biological activity, such as stimulation of cellular proliferation as measured by 3H thymidine incorporation of stem cells. As shown in FIG. 2, only the Loop C peptide (corresponding to amino acids 33-50) showed significant TGF-α biological activity as compared to data obtained with TGF-α 50 amino acid polypeptide or even the altered splice 57 amino acid polypeptide and is therefore a TGF-α mimetic peptide. Accordingly, data from TGFα or TGF-α57 show what can be called “TGF-α activity” and that these are predictive of activity of the functional TGF-α peptide and similar functional TGF-α peptides embodied in the genus of formula I with or without the addition of a “tail” region of formula II. These data predict activity for the functional TGF-α peptides when activity is also shown for TGF-α or for TGF-α57.

example 2

Hematopoiesis

[0154]TGF-α and related polypeptides, such as TGF-α57, showed surprising enhancing activity in an in vivo model of general hematopoiesis when administered in conjunction with a potent cytotoxic agent Cis Platinum (CP). FIG. 3 shows a graph of mouse spleen weights that were treated with CP at either 5 mg / kg or 10 mg / kg and with TGF-α57 at concentrations of 10 μg / kg or 50 μg / kg. These data show that TGF-α57 treatment caused a return to normal spleen weights despite CP treatment that reduced spleen weights significantly. This in vivo experiment is a predictive model for hematopoiesis in humans as CP is a cytotoxic agent commonly used for cancer chemotherapy that is known to significantly reduce trilineage hematopoietic cells. Hematopoietic and myeloid cells are red blood cell precursors, platelet precursors (megakaryocytes), and immune (white) blood cell precursors of various forms of T cells, B cells and macrophages. Moreover, platelet counts were higher in those mice inj...

example 3

Mucositis and Gastrointestinal Diseases

[0160]The small intestine comprises the duodenum, jejunum and ileum. It is the principal site for absorption of digestive products from the GI tract. Digestion begins in the stomach and is completed in the small intestine in association with the absorptive process. The intestinal mucosa surface is made up of numerous finger-like projections called villi. In addition, mucosal epithelium between the basis of the villi is formed into the crypts which contain stem cells.

[0161]TGFα or a peptide from formula I, formula II, formula III, formula IV, formula V, or formula VI having TGFα activity or combinations thereof are also useful for treating mucositis associated intestinal bleeding, dyspepsia caused by with cytotoxic therapy and for improving the barrier function of the GI tract compromised by cytotoxic therapy. The in vivo experiment with seven groups of mice described above for hematopoietic effects noted in spleens also examined the GI tract of...

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Abstract

Disclosed are TGF-α polypeptides, related polypeptides, fragments and mimetics thereof useful in stimulating stem cell or precursor cell proliferation, migration and differentiation. The methods of the invention are useful to treat tissue injury as well as expand stem cell populations in, or obtained from, gastrointestinal, musculoskeletal, urogenital, neurological and cardiovascular tissues. The methods include ex vivo and in vivo applications.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 050,190, filed Jan. 15, 2002, which application issued as U.S. Pat. No. 7,329,645 on Feb. 12, 2008; which application is a continuation of U.S. application Ser. No. 09 / 641,587, filed Aug. 17, 2000, now abandoned, which application is a continuation-in-part of U.S. application Ser. No. 09 / 492,935, filed Jan. 27, 2000, pending, which application is a continuation-in-part of U.S. application Ser. No. 09 / 378,567, filed Aug. 19, 1999, now abandoned; which applications are incorporated herein by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates generally the field of tissue repair and more specifically to the use of transforming growth factor alpha (TGF-α) polypeptide, fragments and mimetics for stimulating stem cells proliferation, migration and differentiation.BACKGROUND[0003]Stem cells and tissue precursor cells play important roles in th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/18A61K38/00C07K14/495
CPCA61K38/00C07K14/495Y02A50/30
Inventor TWARDZIK, DANIEL R.PERNET, ANDREFELKER, THOMAS S.PASKELL, STEFAN
Owner TWARDZIK DANIEL R
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