Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-11-04
2001-03-06
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200
Reexamination Certificate
active
06197751
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to tissue repair and more specifically to methods for regulating wound healing, angiogenesis and cell migration using thymosin &agr;1 (T&agr;1).
BACKGROUND
Impaired tissue healing is a significant problem in health care. Chronic, non-healing wounds are a major cause of prolonged morbidity in the aged human population. This is especially the case in bedridden or diabetic patients who develop severe, non-healing skin ulcers. In many of these cases, the delay in healing is a result of inadequate blood supply either as a result of continuous pressure or of vascular blockage. Poor capillary circulation due to small artery atherosclerosis or venous stasis contribute to the failure to repair damaged tissue. Such tissues are often infected with microorganisms that proliferate unchallenged by the innate defense systems of the body which require well vascularized tissue to effectively eliminate pathogenic organisms. As a result, most therapeutic intervention centers on restoring blood flow to ischemic tissues thereby allowing nutrients and immunological factors access to the site of the wound.
Wounds (i.e., lacerations or openings) in mammalian tissue result in tissue disruption and coagulation of the microvasculature at the wound face. Repair of such damage represents an orderly, controlled cellular response to injury. All soft tissue wounds, regardless of size, heal in a similar manner. Tissue growth and repair are biologic systems wherein cellular proliferation and angiogenesis occur.
Although many of the basic biochemical steps in wound healing have been characterized, a number of key regulatory factors have yet to be identified. The identification of such factors could lead to improved methods for the treatment of disease states associated with ineffectual wound healing. In wound healing, lymphoid cells release soluble factors that attract fibroblasts and macrophages initiating repair, endothelial cell migration, angiogenesis and matrix production.
An important aspect of wound repair is the revascularization of damaged tissue by angiogenesis. The process of angiogenesis involves endothelial cell attachment, basement membrane degradation and synthesis, migration and proliferation. Mitogenic factors released from lymphoid and endothelial cells can induce angiogenesis and promote neovascularization of damaged tissue. Regulation of angiogenesis is of considerable significance in tissue formation, wound healing and in pathological conditions such as cancer, Wegener's granuloma, Takayasu's arteritis, systemic lupus erythematosus and other autoimmune diseases.
Previous studies have used the “scratch” wound closure assay to assess the potential effects of an agent on in vitro cell migration. Though informative, such a test does not mimic in vivo wound healing conditions to the extent that all factors involved in wound closure are present in the assay. For this reason, in vivo systems have been developed to assess the ability of an agent or factor to modulate wound healing activities.
T&agr;1 was initially identified as an immunomodulatory factor which affects T-cell maturation, differentiation and function in vitro and in vivo. T&agr;1 can enhance the production of IL-2 and a-IFN and upregulate the expression of IL-2 receptors on mitogen-stimulated T-cells. In addition, T&agr;1 has important actions outside the immune system related to a role for this peptide and its 113 amino acid parent molecule, prothymosin &agr;, in regulating cell proliferation and apoptosis (Sburlati et al.,
Proc. Natl. Acad. Sci.
88:253, 1991).
SUMMARY OF THE INVENTION
The present invention is based on the discovery that thymosin &agr;1 (T&agr;1) accelerates wound healing and stimulates angiogenesis. The invention is further based on the discovery that T&agr;1 enhances the morphological differentiation of endothelial cells and is a potent chemoattractant for endothelial cells and monocytes.
In a first embodiment, the invention provides a method for accelerating wound healing in a subject in need of such treatment including contacting the site of the wound with a therapeutically effective amount of a composition containing thymosin &agr;1 peptide.
In another embodiment, the invention provides a method for modulating angiogenesis in a tissue including contacting the tissue with a therapeutically effective amount of a composition containing thymosin &agr;1 peptide.
In another embodiment, the invention provides a method of inhibiting angiogenesis in a subject, including administering to the subject a composition containing an agent which regulates thymosin &agr;1 activity.
In yet another embodiment, the invention provides a method of diagnosing a pathological state in a subject suspected of having pathology characterized by a cell proliferative disorder associated with thymosin &agr;1, including obtaining a sample suspected of containing thymosin &agr;1 from the subject, determining the level of thymosin &agr;1 in the sample and comparing the level of thymosin &agr;1 in the sample to the level of thymosin &agr;1 in a normal standard sample.
In another embodiment, the invention provides a method for ameliorating a cell proliferative disorder associated with thymosin &agr;1, including treating a subject having the disorder, at the site of the disorder, with a composition which regulates thymosin &agr;1 activity.
REFERENCES:
patent: 4650674 (1987-03-01), Aggarwal et al.
patent: 5308833 (1994-05-01), Scharschmidt et al.
patent: 5468737 (1995-11-01), McAnalley et al.
patent: 5514555 (1996-05-01), Springer et al.
patent: 5556645 (1996-09-01), Bockman et al.
patent: 5574026 (1996-11-01), Backer et al.
patent: 5585352 (1996-12-01), Goldstein et al.
patent: 5629292 (1997-05-01), Rodgers et al.
patent: 5632983 (1997-05-01), Hadden
patent: 5686425 (1997-11-01), Lee et al.
Frillings et al. Appearance of Thymosin ∝1 in Supernatants . . . Arch. Biochem. Biophys. vol. 296, No. 1, pp. 256-263, Jul. 1992.
Frohm et al., “Biochemical and antibacterial analysis of human wound and blister fluid”Eur. J. Biochem., 237, 86-92, 1996.
Grant et al., “Matrigel induces thymosin &bgr;4 gene in differentiating endothelial cells”Journal of Cell Science, 108, 3685-3694, 1995.
Malinda et al., “Thymosin &bgr;4 stimulates directional migration of human umbilical vein endothelial cells”Thyomosin &bgr;4, Enhances Endothelial Cell Migration, 474-481, 1997.
Goldstein Allan L.
Kleinman Hynda K.
Malinda Katherine M.
Fish & Richardson P.C.
Russel Jeffrey E.
The United States of America as represented by the Department of
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