Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-05-24
2003-12-30
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S566000, C514S081000, C514S049000, C514S560000, C514S715000
Reexamination Certificate
active
06670397
ABSTRACT:
BACKGROUND OF THE INVENTION
Multiple invertebrates and several vertebrate species are known to possess the ability to regenerate lost body parts (Goss,
Clin. Orthop
., 1980, 151:270-282; Kawamura and Fujiwara,
Sem. Cell Biol
., 1995, 6:117-126; Tsonis,
Devel. Biol
., 2000, 221:273-284). Thus, invertebrates can reconstruct the whole body from small pieces (Kawamura and Fujiwara, supra). Examples of regeneration in vertebrates include (i) rabbits and bats which can fill in holes punched through their ears; (ii) adult salamanders which can regenerate a complete limb after amputation; and (iii) mice which can replace the tip of a foretoe when it is amputated distal to the last joint (Goss and Grimes,
Am. Zool
., 1972, 12:151; Neufeld and Zhao, pp.243-252, In:
Limb Development and Regeneration
, Fallon ed., John Wiley and Sons, 1993).
In humans, the fingertips of young children have also been shown to regrow after amputation distal to the last joint (Goss, supra; Illingworth,
J. Ped. Surg
., 1974, 9:853-858). Two factors have been shown to be important for this regeneration: (1) the opened surface of a fresh wound that can be covered by epidermal epithelium originating from the margins of the amputation site (Stocum, pp.32-53, In:
Regulation of Vertebrate Limb Regeneration
, Sicard ed., Oxford Univ. Press, 1985), and (2) an adequate nerve supply at the wound surface (Singer et al.,
Anat. Embryol
., 1987, 177:29-36).
The cellular mechanisms underlying regeneration have been studied for a number of years, and there appear to be some conserved features between species. In vertebrates, there are two ways in which regeneration occurs. In some tissues, multipotent quiescent stem cells become activated by damage and proliferate to produce new cells of several different terminally differentiated phenotypes. Alternatively, there may be a change in the phenotype of the functional, fully differentiated cells, such that they lose many of their differentiated characteristics, and proliferate to form new fully differentiated cells of other phenotype. This latter process has been termed “transdifferentiation” (Okada, pp.349-380, In:
Current Topics in Developmental Biology
, Denis-Donini et al. eds., Acad. Press, 1980; Okada,
Trans
-
differentiation
, Oxford Sci. Publ., 1991).
Retinal regeneration represents an example of the regenerative process that can occur either through stem cells or via transdifferentiation, depending on the species. Thus, teleost fish contain a population of retinal progenitor stem cells that can act as a source of new retinal neurons following damage (Hitchcock and Raymond,
Trends Neurosci
., 1992, 15:103-108). In contrast, amphibians and embryonic chicks can regenerate their retina by a process that involves transdifferentiation of the cells in the pigment epithelium (RPE) to neural retinal progenitors (Reh and Pittack,
Sem. Cell Biol
., 1995, 6:137-142).
The existence of regeneration by transdifferentiation was questioned for a long time as it was not consistent with the classic view of differentiation, according to which a once acquired cellular phenotype was considered to be fixed due to irreversible changes in the gene expression pattern. However, the development of in vitro cell culture systems allowed the unequivocal experimental demonstration of regeneration by transdifferentiation. Thus, it has been shown that cultured fully differentiated pigmented epithelial cells of adult newt iris have the ability to dedifferentiate and proliferate to form a new tissue, lens (Eguchi et al.,
Proc. Natl. Acad. Sci. USA
, 1974, 70:5052-5056; Abe and Eguchi,
Dev. Growth Diff
., 1977, 19:309-317).
Both in vivo and in vitro studies have demonstrated that cytoplasmic signals and changes in the gene expression (e.g., selective gene activation and/or silencing) caused by interactions with growth factors and components of the extracellular matrix are important in the control of cellular transdifferentiation (Kodama and Eguchi,
Sem. Cell Biol
., 1995, 6:143-149; Rao and Reddy, ibid., 151-156). Thus, it has been shown that copper deficiency in rats leads to loss of cell-cell interactions, altered microenvironment and global apoptosis of acinar cells in the pancreas which, in turn, causes oval and ductal pancreatic cells to undergo active proliferation resulting in their transdifferentiation into liver hepatocytes (Rao and Reddy, supra). In another series of experiments conducted with the neural crest-derived pigmented skin cells (chromatophores) of the Axolotl (
Ambystoma mexicanum
), it has been shown that the addition of guanosine can cause these cells to transdifferentiate from one pigmented cell type to another (Frost et al.,
Pigm. Cell Res
., 1987, 1:37-43; Thibaudeau and Holder,
Pigm. Cell Res
., 1998, 11:38-44).
It is believed that the replacement of complex appendages (i.e., epimorphic regeneration) following amputation in lower vertebrates also occurs by transdifferentiation (Goss, supra). Thus, during epimorphic regeneration, epidermal wound healing is followed by the accumulation of dedifferentiated blastemal cells beneath the wound epidermis. These blastemal cells are thought to originate by the dedifferentiation of the mesenchymal and Schwann cells of the stump tissue (Brockes,
Science
, 1984, 225:1280-1287) which then redifferentiate to reconstruct the limb tissue (Singer et al.,
Anat. Embyol
., 1987, 177:29-36).
SUMMARY OF THE INVENTION
The present invention is directed to methods for inducing mammalian cells to transdifferentiate and to uses of such cells. Cells which display morphological and functional characteristics representative of terminal differentiation are induced to change into other cell types. These cells may be derived from a plurality of organisms and from any body tissue.
In one aspect, the present invention provides a method for transdifferentiating mammalian cells comprising the steps of:
(a) contacting said cells with an effective amount for dedifferentiation of an agent which causes dedifferentiation of said cells, producing dedifferentiated cells;
(b) contacting said dedifferentiated cells of step (a) with an amount effective for transdifferentiation of an agent which causes transdifferentiation of said dedifferentiated cells;
(c) contacting said cells from step (b) with an amount effective for stabilization of an agent which causes stabilization of cells produced in step (b); and
(d) recovering stabilized, transdifferentiated cells.
In another aspect, the present invention provides a method for regenerating or creating a developmental field in a remnant of a structure in a mammal, said structure having been partially destroyed, comprising the steps of:
(a) dedifferentiating said remnant of said structure;
(b) transdifferentiating said remnant of said structure of step (a); and
(c) stabilizing said remnant of said structure of step (b); thereby creating a developmental field in said remnant.
In yet another aspect, the present invention provides a method for treating cancer in a mammal comprising contacting said cancer with an amount or an agent effective to cause transdifferentiation of said cancer into benign cells.
In a further aspect, the present invention, the present invention provides a method for inhibiting the progression of an antibody-mediated autoimmune disease in a patient comprising the steps of:
(a) obtaining cells from said patient of the type which are under autoimmune attack;
(b) contacting said cells with an amount of a transdifferentiation agent effective to convert said cells to a normal phenotype;
(c) culturing said converted cells in vitro to amplify said cells;
(d) immobilizing said cells on a membrane which allows blood to enter but retains the cell; and
(d) contacting said immobilized cells with said patients' blood, thereby removing said antibodies from said patients' blood.
In a still further aspect, the present invention provides a method for regenerating a tissue or organ in the body of a mammal, wherein said tissue or organ is damaged due to injury or is missing, comprising the steps of.
(a)
Darby & Darby
Travers Russell
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