Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-04-05
2004-03-16
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S326000, C530S327000, C530S328000
Reexamination Certificate
active
06706685
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to compounds and methods for use in stimulating &bgr;-catenin mediated gene expression and cellular differentiation. The invention is more specifically related to modulating agents capable of increasing the level of free &bgr;-catenin in a cell cytoplasm, and to therapeutic methods employing such agents.
BACKGROUND OF THE INVENTION
&bgr;-catenin is a cytoplasmic protein that is critical for classical cadherin-mediated intercellular adhesion. Inside the cell, a &bgr;-catenin/(&agr;-catenin complex interacts with the second cytoplasmic domain (CP2) of the classical cadherins. In the absence of this &bgr;-catenin/&agr;-catenin complex, the classical cadherins cannot promote cell adhesion (see Wheelock et al.,
Current Topics in Membranes
43:169-185, 1996).
In addition to its role in cell adhesion, &bgr;-catenin also appears to be a key component of certain cellular signaling pathways, leading to activation of gene expression and a variety of developmental processes, such as differentiation. In particular, &bgr;-catenin functions in Wnt-mediated signaling, associating with LEF-1/TCF DNA binding proteins to form a transcription factor (see FIG.
2
). The level of signal transduction appears to correlate with the level of free &bgr;-catenin in the cytoplasm of the cell (see Willert and Nusse,
Genetics and Development
8:95-102, 1998). Glycogen synthase kinase 3&bgr;(GSK-3&bgr;) and adenomatous polyposis coli tumor suppressor protein (APC) interact with cytoplasmic &bgr;-catenin and facilitate its degradation via the ubiquitin/proteosome pathway (see FIG.
2
).
Wnt-mediated signaling is involved in a variety of developmental processes, including cellular differentiation. For example, skin cells expressing a stabilized form of &bgr;-catenin display increased hair growth (Gat et al.,
Cell
95:605-614, 1998; Ono et al.,
Cell
95:575-578, 1998). Thus, therapies based on increasing the level of free &bgr;-catenin in the cytoplasm have potential for stimulating Wnt-mediated signal transduction, resulting in differentiation and, in certain instances, enhanced hair growth. However, there are presently no available therapies for modulating Wnt-mediated signaling.
Accordingly, there is a need in the art for improved methods for inducing Wnt-mediated signal transduction and cellular differentiation. The present invention fulfills this need and further provides other related advantages.
SUMMARY OF THE INVENTION
The present invention provides methods for stimulating &bgr;-catenin mediated gene transcription and cellular differentiation. Within certain aspects, the present invention provides modulating agents capable of increasing the level of free &bgr;-catenin in a cell. In one such aspect, the modulating agent comprises an internalization moiety and one or more of: (a) the amino acid sequence SYLDS(PO
4
)GIHS(PO
4
)G (SEQ ID NO:1) or (b) a peptide analogue or peptidomimetic of the amino acid sequence SYLDS(PO
4
)GIHS(PO
4
)G (SEQ ID NO: 1). The internalization moiety may comprise, within certain embodiments, an internalization sequence covalently linked to the modulating agent, a liposome that encapsulates the modulating agent or an antibody or ligand that binds to a cell surface receptor. Within further embodiments, any of the above modulating agents may be linked to a targeting agent and/or a drug.
Within other aspects, the present invention provides pharmaceutical compositions comprising a modulating agent as described above, in combination with a pharmaceutically acceptable carrier.
The present invention further provides, within other aspects, methods for increasing the level of &bgr;-catenin in a cell, comprising contacting a cell with a modulating agent as described above.
Within further related aspects, the present invention provides methods for stimulating the activation of &bgr;-catenin mediated gene transcription in a cell, comprising contacting a cell with a modulating agent as described above.
Within further related aspects, the present invention provides methods for stimulating differentiation of a cell, comprising contacting a cell with a modulating agent as described above. In certain embodiments, the cell is a skin cell, such as a keratinocyte.
In other aspects, methods are provided for stimulating hair growth or reducing hair loss on a mammal, comprising administering to a mammal a modulating agent as described above. Such administration may be topical, and the skin cells may be present, for example, on the scalp or within the ear of the mammal.
The present invention further provides, within other aspects, methods for stimulating exfoliation of skin on a mammal, comprising administering to a mammal a modulating agent as described above.
REFERENCES:
patent: 5631237 (1997-05-01), Dzau et al.
patent: 5652122 (1997-07-01), Frankel et al.
patent: WO 98/45319 (1997-04-01), None
patent: WO 98/42296 (1998-10-01), None
patent: WO 99/00138 (1999-01-01), None
patent: WO 99/42481 (1999-08-01), None
Yanin Bidault, “The next generation of bioinformatics software: Examining proteins on the desktop computer”, American Biotechnology Laboratory, p. 12, Jan. 2002.*
Huber et al., Nuclear localization of b-catenin by interaction with transcription factor LEF-1, Mechanisms of Development (1996) 59:3-10.*
Remington, J. P. Remington's Pharmaceutical Sciences. PA, Mack Publ. Co., 1990 p. 1692.*
Aberle et al., “&bgr;-catenin is a target for the ubiquitin-proteasome pathway,”The EMBO Journal 16(13):3797-3804, 1997.
Easwaran et al., “The Ubiquitin/Proteosome Pathway And Apc Regulation of Beta-Catenin/Lef Signaling,”Mol. Biol. Cell 9:248a, Abstract No. 1440, 1998.
Gat et al., “De Novo Hair Follicle Morphogenesis and Hair Tumors in Mice Expressing a Truncated &bgr;-Catenin in Skin,”Cell 95:605-614, 1998.
Hall et al., “Inhibition of FGF-stimulated phosphatidylinositol hydrolysis and neurite outgrowth by a cell-membrane permeable phosphopeptide,”Current Biology 6(5):580-587, 1996.
Longer, Mark A., “Sustained-Release Drug Delivery Systems,” Remington's Pharmaceutical Sciences, 18thEd., Chapter 91, pp. 1676-1693, 1990.
Mims et al., “A Nonexchangeable Apolipoprotein E Peptide That Mediates Binding to the Low Density Lipoprotein Receptor,”The Journal of Biological Chemistry 269(32):20539-20547, 1994.
Oro and Scott, “Splitting Hairs: Dissecting Roles of Signaling Systems in Epidermal Development,”Cell 95:575-578, 1998.
Oxford et al., “Serine Phosphorylation-regulated Ubiquitination and Degradation of &bgr;-Catenin,”The Journal Of Biological Chemistry 272(40):24735-24738, 1997.
Salomon et al. , “Regulation of &bgr;-Catenin Levels and Localization by Overexpression of Plakoglobin and Inhhibition of the Ubiquitin-Proteasome System,”The Journal of Cell Biology 139(5):1325-1335, 1997.
Willert and Nusse, “&bgr;-catenin: a key mediator of Wnt signaling,”Current Opinion in Genetics and Development 8:95-102, 1998.
Zhang et al., “Destabilization of &bgr;-catenin by mutations in presenilin-1 potentiates neuronal apoptosis,”Nature 395:698-702, 1998.
Blaschuk Orest W.
Byers Stephen
Gour Barbara J.
Adherex Technologies Inc.
Low Christopher S. F.
Mitra Rita
SEED Intellectual Property Law Group PLLC
LandOfFree
Compounds and methods for stimulating &bgr;-catenin mediated... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds and methods for stimulating &bgr;-catenin mediated..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds and methods for stimulating &bgr;-catenin mediated... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3209593