Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-22
2003-01-28
Cook, Revecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S315000, C514S428000
Reexamination Certificate
active
06511979
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention includes methods for treating conditions modulated by lactosylceramide and, more particularly, to the use of one or more compounds that enhance UDP-galactose, GlcCer, &bgr;1→4 galactosyltransferase (GalT-2) activity to treat a subject suffering from or susceptible to a condition caused or contributed to by lactosylceramide. The present invention also relates to methods for detecting and analyzing compounds with therapeutic capacity to treat such conditions.
2. Background
Inappropriate cell proliferation in an organism can modulate the development or severity of a variety of conditions. For example, there is recognition that certain conditions can be treated or prevented by increasing cell proliferation in adult or pre-adult animals. In particular, it has been proposed that conditions relating to infection, ulceration, degeneration (e.g., apoptotic and necrotic cell death), aging, hematopoiesis, angiogenesis, certain immune responses, cell and tissue repair can be positively impacted by increasing the proliferation of specified cells. See generally Alberts, B. et al. (1989) in
Molecular Biology of the Cell
2
nd
ed. Garland Publishing Co. (New York and London); Kandel, E. R et al. (1991) in
Principles of Neuroscience
, Apppleton & Lange, (Norwalk, Conn.); Cold Spring Harbor Conf.
Cell Proliferation
(1979), Cold Spring Harbor Laboratories, (New York);
Tissue Growth Factors
, (1981) R. Baseega, ed., (Springer-Verlag, New York).
The proliferation of particular animal cells has attracted interest. For example, the proliferation of smooth-muscle cells (SMCs), epithelia, and other intima has been reported to effect vascular development and integrity, e.g., as in vascular malformation and formation of vascular lesions. In addition, the proliferation of certain skin cells is believed to enhance responses to various traumata such as wounding (e.g., following thermal injury). It is particularly recognized that SMCs and epithelia have significant roles in angiogenesis. See e.g.,
Tissue Growth Factors
, supra; Folkman and Shing (1992),
J. Biol. Chem
. 267: 10931.
The proliferation of cells associated with heart, brain, liver, kidney, eye and other organs has also attracted attention. For example, it has been suggested that increasing numbers of specified cells can treat or prevent certain neurodegenerative diseases such as those impacting the central and peripheral (e.g., motor) systems. Degenerative diseases of the retina and other eye structures can lead to progressive deterioration of vision. In particular, age-related macular dystrophies (e.g., Stargardt disease) are believed to be negatively impacted by inappropriate proliferation of certain cells, e.g., macula. It is has been proposed that the effect of many, if not all neurodegenerative disorders can be offset by enhancing the proliferation of specified cells. See e.g., Kusiak, J. W et al (1996)
Mol. Chem. Neuropathol
. 153; Kandel, E. R et al. supra; Neary et al. (1996)
Trends Neurosci
. (1996) 13.
There has been recognition that inappropriate cell adhesion can also contribute to some conditions. For example, it has been suggested that blood coagulation is enhanced by adhesion of platelets and perhaps other blood cells to injured vessels. In addition, certain immune responses, e.g., inflammation associated with rejection of foreign bodies, and recruitment of immune cells are believed to be enhanced in many cases by cell adhesion. Increased adhesion of certain cells may also augment angiogenesis following trauma, during development or following grafting.
A variety of synthetic, semi-synthetic and naturally-occurring cell molecules have been reported to play significant roles in animal cell proliferation. Such molecules include certain cytokines, growth factors, cell receptors, matrix molecules, enzymes, second messenger molecules (e.g., cyclic nucleotides) transcription factors, and mitogens such as phorbol esters.
Other molecules such as adhesion molecules appear to have significant roles in initiating and maintaining suitable cell-to-cell contact.
More particularly, molecules with capacity to modulate cell pathways comprising glycosphingolipids (GSLs).have attracted substantial interest. The GSLs have been reported to have roles in the proliferation and adhesion of animal cells among other functions. See e.g., Chatterjee, S.,
Biochem. Biophys. Res Comm
. (1991) 181:554; Hakomori, S. I. (1983) in
Sphingolipid Chemistry
, eds. Kanfer, J. N. and Hakomori, S. I. (Plenum Press, New York); Obeid, L. M et al. (1993)
Science
259: 1769 and references cited therein.
Specific cell pathways relating to GSLs such as glucosylceramide (GlcCer) and lactosylceramide (LacCer) have been disclosed. For example, one pathway involves synthesis of GlcCer by coupling UDP-glucose to ceramide in a reaction catalyzed by UDP-glucose glucosyltransferase (GlcT-1). Another step converts the GlcCer to LacCer using UDP-galactose, GlcCer, &bgr;1→4 galactosyltransferase (GalT-2). See e.g., Chatterjee et al. supra.
Attempts have been made to inhibit the steps involving GlcT-1. For example, it has been reported that the D-enantiomer of 1-phenyl-2-decanolylamino-3-morpholino-1-propanol (D-PDMP) inhibits GlcT-1 and reduces proliferation of vascular cells. The mechanism of PDMP action has been reported to be unclear. See e.g., Felding-Habermann, B., et al. (1991)
Biochemistry
29:6314; Shukla, G. S. et al.
Biochem. Biophys. Acta
. (1991) 1083:101; Inokuchi, J. et al.,
J. Lipid. Res
. (1987) 28:565; and Chatterjee, S., supra.
Specified morpholinoceramides also have been disclosed as GlcT-1 inhibitors. See Carson, K. and B. Ganem (1994)
Tetrahedron Lets
. 35:2659.
Increased levels of LacCer are believed to enhance the proliferation of certain animal cells such as aortic smooth-muscle cells and specified melanoma cells. See e.g., Chatterjee, S., supra and Noirijiri, H. Et al (1988)
J. Biol. Chem
. 263:443.
Thus, it would be desirable to have effective methods of modulating levels of LacCer e.g., by enhancing GalT-2 activity. In particular, it would be useful to have therapeutic methods of increasing LacCer levels to treat or prevent conditions or diseases impacted by lactosylceramides.
SUMMARY OF THE INVENTION
We have now discovered therapies to treat or prevent various conditions or diseases modulated by lactosylceramide (LacCer). In particular, we have discovered therapies that include increasing activity of UDP-galactose, GlcCer, &bgr;1→4 galactosyl-transferase (GalT-2).
More specifically, the invention provides methods for treatment or prevention of conditions or diseases impacted by increased cell proliferation or adhesion, e.g., tissue repair, ulceration, blood coagulation, infection, degeneration (e.g., apoptotic and necrotic cell death), angiogenesis, aging and certain immune responses and chemoattraction.
Therapies of the invention are particularly effective for enhancing tissue repair and for the treatment or prevention of undesired degeneration particularly involving cells such as neurons of the central (CNS) or peripheral (PNS) nervous system including the eye. In one protocol of the invention, an increase in cell proliferation following cell or tissue contact with one or more compositions of the invention can be observed, whereas a control exhibits much less proliferation. In particular, the present invention features a variety of in vitro and in vivo protocols for testing the compositions as set forth in the discussion and examples which follow.
LacCer-modulated conditions that can be enhanced in accordance with the invention also include angiogenesis (neovascularization); and response to various traumata e.g., ulceration of smooth muscle and related cells; tissue repair, particularly in response to burning or an incision; and grafting.
Therapeutic methods of the invention in general comprise administering to a subject, particularly a mammal such as a primate and especially a human, in need of treatment a therapeutically effective amount of a compoun
Buchanan Robert L.
Cook Revecca
Corless Peter F.
Johns Hopkins University
Rees Dianne M.
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