Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-25
2002-11-26
Nguyen, Dave T. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S455000, C435S456000, C435S320100
Reexamination Certificate
active
06486133
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of enhancing the repair of wounds in mammalian tissue, e.g., following injury, burn, surgery and skin grafting or tissue transplantation, and inducing neovascularization therein.
BACKGROUND OF THE INVENTION
Wound repair and tissue generation in normal and impaired wound healing conditions is a major focus in medicine. In particular, the capability to achieve wound healing or develop tissue growth in an impaired wound healing, environment remains a problem. The mechanisms of normal wound healing, hypertrophic and keloid scarring, as well as the generation of new tissue growth have been postulated to be related, particularly at the growth factor level. The potential for growth factors to enhance wound healing, soft tissue generation, scar manipulation, and tumor activity has stimulated intense investigative efforts over the past few years. Unfortunately, these studies have yet to provide a clinically effective delivery system or clinically significant results in human skin.
Experimental evidence suggests that human vascular endothelial growth factor (VEGF), for example, has an important function in the maintenance of the vasculature in healthy tissues, in wound healing and in angiogenesis. VEGF is a potent mitogen for endothelial cells, and causes cytoplasmic accumulation of calcium, changes in cell morphology, an increase in cell division, and altered gene expression (up-regulates proteases). VEGF also inhibits the maturation of dendritic cells, permeabilizes vascular beds (VEGF enhances vesicular-vacuolar organelles) and is responsible for the autocrine growth of AIDS-Kaposi sarcoma cells.
At low levels, VEGF is expressed by a variety of normal cells including keratinocytes [C. P. Kiritsy and S. E. Lynch, 1993,
Crit. Rev. Oral Biol. Bed.,
4:729-760] and macrophages in the healing of cutaneous wounds. VEGF is also found in the endometrium and corpus luteum; is produced by podocytes or renal glomerulus, by prostatic epithelium and by epithelial cells of the adrenal cortex and lung. VEGF is upregulated during wound healing, psoriasis and delayed type hypersensitivity. It is produced by cardiac myocytes in ischemic myocardium and by synovial lining cells in the pannus of rheumatoid arthritis. It is constitutive in many tumors, such as tumors of the colon, stomach, pancreas, kidney, bladder, breast and glioblastoma. Most malignant cells, including melanoma cells, express VEGF. Its expression can be induced by other growth factors, such as transforming growth factor (TGF-&bgr;) and platelet derived growth factor (PDGF) and cytokines, or by hypoxic environmental conditions [S. A. Eming el al, 1995,
J. Invest. Dermatol.,
105:756-763]. Its over expression leads to hypervascularization which is often associated with chronic inflammatory diseases and cancer [see, e.g., F. Grinnel, 1992,
J. Cell Sci.,
101:1-5, V. Falanga el al, 1994,
J. Invest. Dermatol.,
102:125-127; G. F. Pierce et al, 1991,
J. Cell. Biol.,
45:319-326].
A variety of VEGF constructs and uses in neovascularization and wound healing have been proposed. For example, see International Patent Application WO96/26736, published Sep. 6, 1996, which relates to VEGF-B proteins useful to accelerate angiogenesis in wound healing, International Patent Application WO95/24473, published Sep. 14, 1995, relates to VEGF-&bgr;polypeptide, useful for wound healing and periodontal disease; European Patent Application No. 550296, published Jul. 7, 1993 relates to VEGF protein, used for promoting angiogenesis in treatment of cardiac angiopathy, wounds, burn injuries, postoperative tissue damage, etc.; U.S. Pat. No. 5,219,739, issued Jun. 15, 1993, relating to DNA sequences, vectors and transformed cells for producing VEGF for treating wounds European Patent Application No. 506477, published Sep. 30, 1992, relating to VEGF sub-units for inducing tissue repair and growth; European Patent Application No. 476983, published Mar. 25, 1992, and relating to VEGF 11 for coating blood vessels or to promote tissue repair; U.S. Pat. No. 5,073,492, issued Dec. 17, 1991; and U.S. Pat. No. 5,194,596, issued Mar. 16, 1993, among others.
The use of replication deficient adenovirus vectors (Ad) to deliver VEGF to heart, smooth muscle and endothelial cells, as well as delivery of such vectors via subcutaneous injection has been the subject of much experimentation. For example, replication defective adenoviruses carrying VEGF genes have been described in, e.g., J. Muehihauser et al, 1995,
Circul. Res.,
77(6):1077-1086 and J. Muhlhauser et al, 1994,
J. Cell. Biochem
., Supp. 0 (18 Part A), p. 239. The Muhlhauser references refer to the delivery of a replication deficient adenovirus carrying a human VEGF-165 gene under the control of the cytomegalovirus promoter to human umbilical vein endothelial cells and rat aorta smooth muscle cells. The same vector was injected subcutaneously in mice, and two weeks post injection, histological evidence of neovascularization in the tissue surrounding the site of injection was observed. Similarly, C. J. Magovern et al, 1996,
Annals Thor. Sure.,
62(2):425-434 refers to the use of a replication defective Ad carrying the gene for VEGF in direct myocardial injection to accomplish gene transfer. These authors noted sustained and localized expression of VEGF for up to 7 days after a single injection, and posited that this strategy may be used to stimulate angiogenesis in ischemic myocardium [see, also, R. Ziegelstein et a/, 1994,
Circul.,
90(4), part II, p. 1899].
The principal growth factor found in platelets as well as macrophages, fibroblasts and endothelial cells is platelet derived growth factor (PDGF), a 30 Kda protein dimer existing in three different isoforms (PDGF-AA, PDGF-AB and PDGF-BB), which is released at a site of injury within the body. The mitogenic effects of PDGF-BB isoform, which can bind to the PDGF-&bgr; receptor, on fibroblasts, smooth muscle cells and other mesenchymal cells have been extensively documented. The chemoattractive effects mediated through the PDGFB receptor have implicated PDGF-BB and PDGF-AB in the physiologic process of wound healing and tissue repair and the pathologic process of atherosclerosis.
PDGF-BB has been shown to be an integral part of the initial and early stages of wound healing, with its participation in the inflammation and granulation tissue stages respectively. PDGF-BB was also shown to be present in wounds and also within the blister fluid of burn patients. The final stage of wound healing, in which scar tissue remodelling occurs, can largely be attributed to the autocrine production of PDGF-BB from dermal fibroblasts. Such autocrine loops are initially stimulated in a paracrine fashion with platelet PDGF, which ultimately results in the deposition of extracellular molecules such as fibronectin and tenascin. Chondroitin sulfate may also be deposited which may inhibit the action of collagenase. In wound healing it has also been shown that there is also a major reorganization of collagen types I and III. The accumulation of such molecules in connective tissue is associated with diseases such as rheumatoid arthritis and atherosclerosis. This may implicate the involvement of PDGF in the pathogenesis of these diseases. The sequence homology of PDGF-B with a viral oncogene from Simian Sarcoma virus (v-sis), also implicates PDGF-B in normal and neoplastic development, with many tumors being intimately involved with the production of PDGF-BB.
Systematic analyses of the roles of individual growth factors and cytokines for their angiogenic properties have been difficult in disease-related conditions because experimental over expression or suppression of expression of growth factors in human cells could not be achieved consistently under in vivo conditions. Indirect evidence of the potential roles of growth factors came from expression studies in diseased skin in which mRNA or protein levels were determined.
Application of exogenous growth factors to wounds,
Herlyn Meenhard
Nesbit Mark
Satyamoorthy Kapaettu
Howson and Howson
Nguyen Dave T.
Nguyen Quang
The Wistar Institute of Anatomy and Biology
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