41 results about "Wnt signalling" patented technology

Compositions and methods for modulating proliferation and / or lineage commitment of stem cells by modulating the Wnt signalling pathways. Modulators of the Wnt signalling pathways and screening methods to identify modulators are also provided. The methods of the invention may be conducted in vitro or in vivo to induce or inhibit stem cell proliferation and / or lineage commitment, and are particularly useful for in vivo stimulation of proliferation and / or lineage commitment of resident stem cells in a tissue.

This invention relates to methods of inhibiting the growth of cancer cells that overexpress a Wnt protein. The methods comprise contacting the cell with an agent that inhibits binding of the Wnt protein to a Frizzled receptor.

The present invention relates to methods for the induction and a cell to enter the Islet 1+ (Isl1+) lineage and methods for expansion of cells of islet 1+ lineage. One aspect of the present invention relates to methods to induce a cell to enter the islet 1+ lineage, and more particularly to a method to induce a cell to enter a the Isl1+ lineage to become an Isl1+ progenitor that is capable of differentiating along multiple different lineages such as a endothelial lineage, a smooth muscle lineage or a cardiac lineage. In particular, one embodiment present invention relates to methods to induce a cell to enter the Isl1+ lineage by inhibiting a wnt signalling pathway in the cell. Another aspect of the present invention relates to methods to expand a cell of the Isl1+ lineage, such as a Isl1+ progenitor by activating a wnt signalling pathway in the Isl1+ progenitor. Another aspect of the present invention relates to use of cells of the isl1+ lineage in subjects for therapeutic and preventative treatment of cardiovascular diseases.

The present invention provides in vitro systems for use in identifying modulators of neural differentiation. Also provided are modulators identified by these systems. The present invention further provides methods for identifying a modulator of neural differentiation, a modulator of a Wnt signalling pathway, a modulator of Wnt-dependent neural differentiation, a modulator of a BMP signalling pathway, a modulator of BMP-dependent neural differentiation, a modulator of a Hh signalling pathway, and a modulator of Hh-dependent neural differentiation. Also provided are modulators identified by these methods.

The present invention discloses osteogenic and anti-adipogenic oxysterols. Agents and methods for protecting, blocking or rescuing marrow stromal cells from the inhibitory effects of oxidative stress on their osteoblastic cellular differentiation are disclosed. Exemplary agents include oxysterols alone or in synergistic combinations, as well as hedgehog or Wnt signaling activators. The synergistic effects of oxysterols and bone morphogenic proteins are also disclosed.

The present invention provides reagents, compounds, compositions, and methods relating to novel interactions of the extracellular domain of LRP5, HBM (a variant of LRP5), and / or LRP6 with Dkk, including Dkk-1. The various nucleic acids, polypeptides, antibodies, assay methods, diagnostic methods, and methods of treatment of the present invention are related to and impact on Dkk, LRP5, LRP6, HBM, and Wnt signaling. Dkk, LRP5, LRP6, HBM, and Wnt are implicated in bone and lipid cellular signaling. Thus, the present invention provides reagents and methods for modulating lipid levels and / or bone mass and is useful in the treatment and diagnosis of abnormal lipid levels and bone mass disorders, such as osteoporosis.

Compositions and methods for modulating proliferation and / or lineage commitment of stem cells by modulating the Wnt signalling pathways. Modulators of the Wnt signalling pathways and screening methods to identify modulators are also provided. The methods of the invention may be conducted in vitro or in vivo to induce or inhibit stem cell proliferation and / or lineage commitment, and are particularly useful for in vivo stimulation of proliferation and / or lineage commitment of resident stem cells in a tissue.

The present invention provides in vitro systems for use in identifying modulators of neural differentiation. Also provided are modulators identified by these systems. The present invention further provides methods for identifying a modulator of neural differentiation, a modulator of a Wnt signalling pathway, a modulator of Wnt-dependent neural differentiation, a modulator of a BMP signalling pathway, a modulator of BMP-dependent neural differentiation, a modulator of a Hh signalling pathway, and a modulator of Hh-dependent neural differentiation. Also provided are modulators identified by these methods.

An ex vivo method for preparing a population of induced paraxial mesoderm progenitor (iPAM) cells includes culturing pluripotent cells in an appropriate culture medium that includes an effective amount of an activator of the Wnt signalling pathway.

The present disclosure provides methods and kits for the differentiation of stem cells into relevant liver cell lineages, as well as methods of using the relevant liver cell lineages in screening for a cellular response, a phenotype and in the treatment of a condition. In one embodiment, stem cells are first differentiated into cells of the definitive endoderm lineage, which are differentiated into posterior foregut (PFG) lineage cells by one or more of retinoic acid activators and / or one or more inhibitors of transforming growth factor-β (TGFβ). An additional embodiment provides a method for the differentiation of posterior foregut lineage cells into liver bud progenitors (LB) by one or more activators of TGFβ signalling, and / or one or more modulators of Wnt signalling, and / or one or more activators of cyclic AMP / PKA signaling; and a further embodiment provides a method for the differentiation of liver bud progenitors into hepatic progenitors by one or more inhibitors of TGFβ signalling and / or fibroblast growth factor (FGF) inhibitors and / or one or more Notch inhibitors. Another embodiment discloses the differentiation of hepatic progenitors into hepatocyte-like cells or perivenous hepatocyte-like cells by one or more of Notch inhibitors and / or activators of glucocorticoid signalling and / or one or more activators of insulin signalling and / or one or more of ascorbic acid signalling activators and / or additional factors. Methods and kits for maintaining LB in self renewal state, hepatocyte-like cells in perivenous or periportal state, as well as surface markers for LB and mid / hindgut (MHG) cells are also disclosed.

The present disclosure provides a method of generating mature mesenchymal stem cells (MSC) from lateral plate mesoderm comprising culturing the lateral plate mesoderm cells on an extracellular matrix in a MSC cell culture media comprising (i) fibroblast growth factor; (ii) platelet-derived growth factor (PDGF); (iii) epidermal growth factor (EGF) and (iv) ascorbic acid. Also claimed are MSCs obtained by said culture method and a method of treating cartilage and bone disease in a patient using said cells. In addition, a culture medium for deriving primitive streak mesendoderm cells from pluripotent stem cells comprising (a) activin; (b) WNT-signalling activator; and / or (c) fibroblast growth factor and a culture medium for deriving lateral plate mesoderm cells from primitive streak mesendoderm cells comprising (1) fibroblast growth factor; (2) bone morphogenetic protein; (3) follistatin; and optionally Rho-associated protein kinase (ROCK) inhibitor are claimed.

Provided are improved methods using Glycogen synthase kinase 3 (GSK3) inhibitors by which endodermal cells, notably endodermal cells derived from human pluripotent stem cells (hPS), such as but not limited to hiPS-cells and hES-cells may be differentiated into hepatocyte like cells. The specific modulation of wingless integration gene (WNT)-signalling pathway and use of GSK3 inhibitors achieve direct differentiation and maturation of hepatocytes derived from human pluripotent stem (hPS) cells. GSK-3 inhibitors, when added to the growth medium at certain developmental stages, leads to more mature and functional features for the hepatocyte like cells as well as more pure and homogenous populations of hepatocyte like cells. Provided are also hepatocyte like cells obtained by these methods as well as compositions comprising them.

The present invention relates to a method of treating or preventing a disease characterized by excessive Wnt signalling, such as colorectal cancer, by administering a compound which inhibits the activity of one or more of JAK2, JAK1 or TYK2.

The present invention relates to methods of diagnosis and treatment of corneal ectasia following refractive surgery, keratoconus or pellucid marginal degeneration in a subject by determining or modulating the level of expression of molecules associated with the Wnt signalling pathway. Marker molecules of the present invention include SFRP1, PITX2, LEF1, WNT16 and WNT5A.

The present invention relates to directed differentiation and maturation of hepatocyte-like cells. In particular, the present invention relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of GSK-3 (Glycogen synthase kinase 3) or activator of Wnt signalling and / or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The present invention also relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of a cycline dependent kinase (CDK) and / or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The hepatocyte-like cells obtained in accordance with the present invention show a phenotype which is more similar to that of primary hepatocytes than previously shown.

The invention discloses methods of differentiating stem cells into liver cell lineages. The present disclosure provides methods and kits for the differentiation of stem cells into relevant Iiver cell lineages, as well as methods of using the relevant Iiver cell lineages in screening for a cellular response, a phenotype and in the treatment of a condition. In one embodiment, stem cells are first differentiated into cells of the definitive endoderm lineage, which are differentiated into posterior foregut (PFG) lineage cells by one or more of retinoic acid activators and / or one or more inhibitors of transforming growth factor-[beta] (TGF[beta]). An additional embodiment provides a method for the differentiation of posterior foregut lineage cells into Iiver bud progenitors (LB) by one or more activators of TGF[beta] signalling, and / or one or more modulators of Wnt signalling, and / or one or more activators of cyclic AMP / PKA signaling; and a further embodiment provides a method for the differentiation of Iiver bud progenitors into hepatic progenitors by one or more inhibitors of TGF[beta] signalling and / or fibroblast growth factor (FGF) inhibitors and / or one or more Notch inhibitors. Another embodiment discloses the differentiation of hepatic progenitors into hepatocyte-like cells or perivenous hepatocyte-like cells by one or more of Notch inhibitors and / or activators of glucocorticoid signalling and / or one or more activators of insulin signalling and / or one or more of ascorbic acid signalling activators and / or additional factors. Methods and kits for maintaining LB in self renewal state, hepatocyte-like cells in perivenous or periportal state, as well as surface markers for LB and mid / hindgut (MHG) cells are also disclosed.

Disclosed herein are biomarkers related to WNT signal transduction pathway, as well as methods and kits comprising the same. Further, the present disclosure relates to the use of the biomarkers in patient selection, companion diagnostics, and treatment of cancer.

The present invention relates to preventing and treating leukemia and diseases and disorders of the blood, by inhibiting canonical Wnt signaling in the osteoblasts. The inhibition is accomplished by blocking specific molecules and receptors in the pathway. The present invention also relates to a method of diagnosing leukemia and disorders of the blood, and methods and assay for drug screening and basic research.

The present invention is directed to the use of macrocyclic lactones, in particular avermectins, in the treatment of conditions whose formation, occurrence, development or growth is associated with aberrant Wnt signalling in particular the treatment of colorectal cancer.

The present invention provides methods of treating ocular disorders with modulators of the WNT signaling pathway. In particular the ocular disorders are retinopathies. Also provided are methods of dosing and pharmaceutical compositions.

The present invention relates to directed differentiation and maturation of hepatocyte-like cells. In particular, the present invention relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of GSK-3 (Glycogen synthase kinase 3) or activator of Wnt signalling and / or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The present invention also relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of a cycline dependent kinase (CDK) and / or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The hepatocyte-like cells obtained in accordance with the present invention show a phenotype which is more similar to that of primary hepatocytes than previously shown.

Provided is a novel soluble factor that modulates morphogenesis and cell proliferation, such as cardiac development and / or cardiomyocyte differentiation. Specifically provided are: an inhibitor of Wnt signalling, comprising an insulin-like growth-factor-binding protein (IGFBP), the protein being binding to a Wnt receptor, and / or a polynucleotide encoding the protein; a medicament for prevention and / or treatment of a disease due to enhanced Wnt signalling, comprising the inhibitor of Wnt signalling, and a medicament for induction of cardiomyocyte differentiation; and a method for prevention and / or treatment of a disease due to enhanced Wnt signalling and a method of inducing cardiomyocyte differentiation, the methods each comprising using the inhibitor of Wnt signalling, and a cardiomyocyte, which is obtained by the method of inducing cardiomyocyte differentiation, and a use thereof.

The present disclosure relates to isolated polypeptides that inhibit Wnt signaling, pharmaceutical compositions comprising the isolated polypeptides, and methods of use thereof. Nucleic acids, cells,and methods of production related to the isolated polypeptides and compositions are also disclosed.

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2 / - / -isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.) and / or Wnt signalling. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to inhibit Wnt signalling; to treat disorders that are ameliorated by the inhibition of PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to treat disorders that are ameliorated by the inhibition of Wnt signalling; to treat proliferative conditions such as cancer, etc.

The invention provides a method of modulating Wnt signalling comprising modulating Trabid activity. Preferably modulating Trabid activity comprises inhibiting; Trabid activity. The invention also provides a method of reducing TCF transcription, said method comprising reducing Trabid activity. A method for identifying a-modulator of Trabid said method comprising; providing a Trabid substrate comprising a detectable moiety coupled to a tag moiety by ubiquitin; immobilizing first and second portions of said substrate; adding a candidate modulator to the first said portion; contacting first and second portions with Trabid; incubating to allow Trabid action, assaying cleavage of ubiquitin by separation of tag from detectable moiety, wherein separation of an amount of detectable moiety from said first portion which is different from the amount of detectable moiety separated from said second portion identifies said candidate as a modulator of Trabid. The invention provides uses of Trabid and of Trabid inhibitors as-medicaments.

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2H-isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.) and / or Wnt signalling. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to inhibit Wnt signalling; to treat disorders that are ameliorated by the inhibition of PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to treat disorders that are ameliorated by the inhibition of Wnt signalling; to treat proliferative conditions such as cancer, etc.

An isolated Shoca polypeptide comprising: (i) the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4; or (ii) a variant thereof which is capable of interacting with a polypeptide of the wnt signalling pathway; or (iii) a fragment of (i) or (ii) which is capable of interacting with a polypeptide of the wnt signalling pathway, a polypeptide encoding said polypeptide, a method for identifying a modulator of the wnt signalling pathway utilising said polypeptide or polynucleotide and methods of diagnosing and treating cancer.

The invention provides a method of modulating Wnt signalling comprising modulating Trabid activity. Preferably modulating Trabid activity comprises inhibiting; Trabid activity. The invention also provides a method of reducing TCF transcription, said method comprising reducing Trabid activity. A method for identifying a-modulator of Trabid said method comprising; providing a Trabid substrate comprising a detectable moiety coupled to a tag moiety by ubiquitin; immobilising first and second portions of said substrate; adding a candidate modulator to the first said portion; contacting first and second portions with Trabid; incubating to allow Trabid action, assaying cleavage of ubiquitin by separation of tag from detectable moiety, wherein separation of an amount of detectable moiety from said first portion which is different from the amount of detectable moiety separated from said second portion identifies said candidate as a modulator of Trabid. The invention provides uses of Trabid and of Trabid inhibitors as-medicaments.

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 3-aryl-5-substituted-2 / - / -isoquinolin-1-one compounds that, inter alia, inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.) and / or Wnt signalling. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to inhibit Wnt signalling; to treat disorders that are ameliorated by the inhibition of PARP (e.g., PARP1, TNKS1, TNKS2, etc.); to treat disorders that are ameliorated by the inhibition of Wnt signalling; to treat proliferative conditions such as cancer, etc.

The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 are negative regulators of β-catenin and Wnt signaling pathways in eukaryotic cells. Antibodies that bind to the extracellular domain of ZNRF3 can modulate the activity of ZNRF3, resulting in enhanced Wnt signaling. ZNRF3 antagonistic antibodies can be used to treat diseases with weak Wnt signaling, such as short bowel syndrome, osteoporosis, diabetes, neurodegenerative diseases and mucositis. Furthermore, the antagonistic antibodies of the present invention can be used to enhance Wnt signaling for tissue repair and wound healing.