Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Patent
1992-01-08
1994-11-08
Robinson, Douglas W.
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
435200, 435195, 435201, C12N 926, C12N 924, C12N 942, C12N 914
Patent
active
053626419
DESCRIPTION:
BRIEF SUMMARY
1. FIELD OF THE INVENTION
The present invention relates to methods and compositions for stimulating the process of wound healing. More specifically, the invention relates to a method of promoting wound healing utilizing compositions comprising a purified form of heparanase.
2. BACKGROUND OF THE INVENTION
2.1. Heparan Sulfate and Related Compounds
The plasma membrane, extracellular matrix, and basement membranes of all tissue types contain, among other constituents, complex macromolecules referred to as heparan sulfate proteoglycans (HSPG). Their function in biological processes is believed to be varied: they appear to be involved in cell-cell recognition, tissue differentiation and morphogenesis, organization of extracellular matrix, permaselective properties, and cell-substrate adhesion. The extracellular matrix appears to be essential to the control of cell proliferation and morphogenesis, and HSPG, as a principal component of basement membranes, plays an integral role in tissue architecture and function.
Proteoglycans are high molecular weight compounds with a protein backbone; linked to the backbone are a number of side chains of different types of heteropolysaccharides. A high proportion of the molecular weight may thus be attributed to carbohydrates. These compounds can routinely be broken down by a number of different enzymes. The degradation of the proteoglycans usually begins with the proteolytic cleavage of the backbone to produce peptide components and glycosaminoglycans. The latter are in turn hydrolysable into smaller glycosaminoglycan fragments by endoglycosidase enzymes, and these are further degradable into monosaccharides by exoglycosidases. Heparan sulfate proteoglycans have an intimate interrelationship with the other macromolecules which make up the extracellular matrix, and thus, their degradation may have a profound effect on the regulation of cell anchorage, movement, function and growth.
2.2. HSPG Degradation
A number of normal and abnormal physiological conditions and disorders have now been shown to be associated with the degradation of the extracellular matrix of various tissues. For example, neutrophil mobilization, as part of the inflammatory process, requires that the cells penetrate the endothelium of blood vessels and the underlying basal lamina in order to reach the target tissue. The penetration requires the specific and mild action of readily released enzymes (i.e., heparanase) expressed by the neutrophils under conditions which maintain the integrity of the vessel wall (Matzner et al., J. Clin. Invest. 76:1306-1313, 1985). Similarly, in the process of metastasis, tumor cells must invade the basal lamina of the vascular endothelium in order to be transported to other sites in the body. T-lymphocytes as well, in responding to the presence of an antigen, will penetrate the walls of blood vessels and subendothelial extracellular matrix. Cell invasion is typically achieved by enzymatic breakdown of the matrix surrounding the cells. The invading cells must, therefore, be capable of producing ECM degrading enzymes whenever necessary to achieve penetration of the wall of the blood vessel or other target tissue.
Since a number of proteoglycans are known to exist as part of the connective tissue, the degrading enzyme could theoretically be any one of a number of enzymes which attack a particular sulfated proteoglycan. For example, depending on the specific tissue involved, the ECM may contain chondroitin sulfate, dermatan sulfate, hyaluronate, keratan sulfate or heparan sulfate, in a characteristic combination. Each of these can be broken down by, respectively, chondroitinase, hyaluronidase, keratanase or heparanase. The ability of a given cell to penetrate a particular tissue type, then, is dependent to a large extent in the production, by the cell, of an enzyme or enzymes which can degrade the proteoglycans in the tissue. HSPG interact with various macromolecules in the ECM, such as collagens, laminin and fibronectin. This suggests a key role for this proteoglycan in t
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Fuks Zvi
Vlodavsky Israel
Hadassah Medical Organization Kiryat Hadassah
Robinson Douglas W.
Sevingny Jeffrey J.
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