Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing
Reexamination Certificate
1995-03-14
2003-05-20
Kemmerer, Elizabeth (Department: 1646)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
C435S325000, C435S363000, C435S366000, C435S370000, C435S372000, C514S002600, C514S012200
Reexamination Certificate
active
06565843
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to morphogenic proteins which can induce tissue morphogenesis in mammals; to methods of identifying these proteins and obtaining them from natural sources or producing synthetic forms of these proteins by expressing recombinant DNA encoding the proteins; to the fabrication of tissue-specific acellular matrices; and to methods for promoting tissue stasis, repair and regeneration, and methods for increasing progenitor cell populations using these proteins.
Cell differentiation is the central characteristic of morphogenesis which initiates in the embryo, and continues to various degrees throughout the life of an organism in adult tissue repair and regeneration mechanisms. The degree of morphogenesis in adult tissue varies among different tissues and is related, among other things, to the degree of cell turnover in a given tissue. On this basis, tissues can be divided into three broad categories: (1) tissues with static cell populations such as nerve and skeletal muscle where there is no cell division and most of the cells formed during early development persist throughout adult life; (2) tissues containing conditionally renewing populations such as liver where there is generally little cell division but, in response to an appropriate stimulus, cells can divide to produce daughters of the same differentially defined type; and (3) tissues with permanently renewing populations including blood, testes and stratified squamous epithelia which are characterized by rapid and continuous cell turnover in the adult. Here, the terminally differentiated cells have a relatively short life span and are replaced through proliferation of a distinct subpopulation of cells, known as stem or progenitor cells.
The cellular and molecular events which govern the stimulus for differentiation of these cells is an area of intensive research. In the medical field, it is anticipated that the discovery of factor(s) which control cell differentiation and tissue morphogenesis will significantly advance medicine's ability to repair and regenerate diseased or damaged mammalian tissues and organs. Particularly useful areas include reconstructive surgery and in the treatment of tissue degenerative diseases including arthritis, emphysema, osteoporosis, cardiomyopathy, cirrhosis, and degenerative nerve diseases.
A number of different factors have been isolated in recent years which appear to play a role in cell differentiation. Some of these factors are gene transcription activators such as the NOTCH gene, identified in Drosophila and the related XOTCH gene identified in Xenopus, as well as a number of transcription activators identified in
Caenorhabditis elegans.
The hemopoietic system, because of its continually renewing cell population, is an area of concentrated study. Factors identified in this system which may be involved in cell renewal include interleukin 3 (IL-3), erythropoietin, the CSFs (GM-CSF, G-CSF, M-CSF et al.) and various stem cell growth factors.
Other proteins thought to play a role in cell differentiation include proteins that are members of the family of insulin-like growth factors (IGF), members of the family of heparin-binding growth factors, (e.g., FGF—acidic and basic fibroblast growth factors, and ECDGF—embryonal carcinoma-derived growth factor) as well as several transforming oncogenes (hst and int-2, see for example, Heath et al., (1988),
J. Cell Sci. Suppl
. 10:256-256.) DIF (Differentiation Inducing Factor), identified in
Dictyostelium discoideum
, is another bioregulatory protein, directing prestock cell differentiation in that organism.
The structurally related proteins of the TGF-&bgr; superfamily of proteins also have been identified as involved in a variety of developmental events. For example, TGF-&bgr; and the polypeptides of the inhibin/activin group appear to play a role in the regulation of cell growth and differentiation. MIS (Mullerian Inhibiting Substance) causes regression of the Mullerian duct in development of the mammalian male embryo, and DPP, the gene product of the Drosophila decapentaplegic complex is required for appropriate dorsal-ventral specification. Similarly, Vg-1 is involved in mesoderm induction in Xenopus, and Vgr-1 has been identified in a variety of developing murine tissues.
Another source that has revealed a wealth of information is in the area of bone morphogenesis. The development and study of a bone model system has identified the developmental cascade of bone differentiation as consisting of chemotaxis of mesenchymal cells, proliferation of these progenitor cells, differentiation of these cells into cartilage, vascular invasion, bone formation, remodeling, and finally, marrow differentiation (Reddi (1981) Collagen Rel. Res. 1:209-206). Proteins capable of inducing endochondral bone formation in a mammal when implanted in association with a matrix now have been identified in a number of different mammalian, species, as have the genes encoding these proteins, (see, for example, U.S. Pat. No. 4,968,590; U.S. Pat. No. 5,011,691; and U.S. Ser. No. 07/599,543, filed Oct. 18, 1990, and subseqently abandoned in favor of U.S. Pat. No. 5,266,683). These proteins, which share significant amino acid sequence homology with one another as well as structural similarities with various members of the TGF-&bgr; super family of proteins, have been shown to induce endochondral bone formation and/or bone cartilage formation when implanted in a mammal in association with a suitably modified matrix. Proteins capable of inducing a similar developmental cascade of tissue morphogenesis of other tissues have not been identified.
It is an object of this invention to provide morphogenic proteins (“morphogens”), and methods for identifying these proteins, which are capable of inducing the developmental cascade of tissue morphogenesis for a variety of tissues in mammals different from bone or bone cartilage. This morphogenic activity includes the ability to induce proliferation and differentiation of progenitor cells, and the ability to support and maintain the differentiated phenotype through the progression of events that results in the formation of adult tissue. Another object is to provide genes encoding these proteins as well as methods for the expression and isolation of these proteins, from either natural sources or biosynthetic sources, using recombinant DNA techniques. Still another object is to provide tissue-specific acellular matrices that may be used in combination with these proteins, and methods for their production. Other objects include providing methods for increasing a progenitor cell population in a mammal, methods for stimulating progenitor cells to differentiate in vivo or in vitro and maintain their differentiated phenotype, methods for inducing tissue-specific growth in vivo and methods for the replacement of diseased or damaged tissue in vivo. These and other objects and features of the invention will be apparent from the description, drawings, and claims which follow.
SUMMARY OF THE INVENTION
This invention provides morphogenic proteins (“morphogens”) capable of inducing the developmental cascade of tissue morphogenesis in a mammal. In particular, these proteins are capable of inducing the proliferation of uncommitted progenitor cells, and inducing the differentiation of these stimulated progenitor cells in a tissue-specific manner under appropriate environmental conditions. In addition, the morphogens are capable of supporting the growth and maintenance of these differentiated cells. These morphogenic activities allow the proteins of this invention to initiate and maintain the developmental cascade of tissue morphogenesis in an appropriate, morphogenically permissive environment, stimulating stem cells to proliferate and differentiate in a tissue-specific manner, and inducing the progression of events that culminate in new tissue formation. These morphogenic activities also allow the proteins to stimulate the “redifferentiation” of cells previously induced to stray from their differentiation
Cohen Charles M.
Kuberasampath Thangavel
Oppermann Hermann
Pang Roy H. L.
Rueger David C.
Curis, Inc.
Kemmerer Elizabeth
Ropes & Gray
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