Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes

A stem cell differentiation and cell technology, applied in the direction of biochemical equipment and methods, fusion cells, embryonic cells, etc., can solve problems such as no indication

Inactive Publication Date: 2005-09-14
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these references do not show that modulating the JNK pathway can be used to regulate the differentiation of stem cells, or can be used to treat myeloproliferative or myelodysplasia disorders

Method used

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  • Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes
  • Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes
  • Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes

Examples

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Effect test

Embodiment 1

[0560] 5.1. Example 1: Effects of JNK or MKK Inhibitors on the Differentiation of CD34+ Progenitor Cells

[0561] The following assays were used to determine the effect of JNK or MKK inhibitors on CD34+ (hematopoietic progenitor) cell differentiation and colony forming unit (CFU) production. Remarkably, this analysis demonstrated that JNK or MKK inhibitors can specifically inhibit the production of erythropoietic colonies (BFU-E and CFU-E), while increasing the production of formed leukocyte and platelet colonies (CFU-GM) and enhancing total colony Production of forming units (total-CFU). The methods of the invention are thus useful for modulating the differentiation of stem cells, and also for stimulating the rate of colony formation, providing significant benefits in favor of hematopoietic stem cell transplantation by improving the rate of bone marrow engraftment and restoration of leukocyte and / or platelet production.

[0562] Cord blood CD34+ hematopoietic progenitor cell...

Embodiment 2

[0564] 5.2. Example 2: Effects of JNK or MKK Inhibitors on the Proliferation and Differentiation of Human Cord Blood CD34+ Cells

[0565] In the following examples, the effect of JNK or MKK inhibitors on the proliferation and differentiation of umbilical cord blood (CB) monocytes into CD34+ (hematopoietic progenitor) cells was investigated. Cord blood mononuclear cells are a mixed cell population including a small population of hematopoietic progenitor (CD34+) cells. A subset of this small CD34+ cell population includes a population of CD34+CD38+ cells (approximately 1% of total CB monocytes) and an even smaller population of CD34+CD38- cells (less than 1% of total CB monocytes ). Significantly, the results can show that CD34+ cells are upregulated (increased differentiation) and inhibit or slow down the differentiation of hematopoietic stem or progenitor cells compared to positive and negative controls.

[0566] Materials and Methods: CB CD34+ cells were started from 20% FC...

Embodiment 3

[0567] 5.3. Example 3: Effects of JNK or MKK Inhibitors on Human Cord Blood Mononuclear Cells

[0568] Cord blood MNCs that had been cryopreserved and thawed using standard methods were isolated by standard Ficoll isolation method and incubated in triplicate in 20% FCS-IMDM with cytokines (IL6, KL and G-CSF 10 ng / ml each) Medium to 0.5×10 6 Cells / ml were cultured in 24-well plates. Experimental groups were no (cytokine only), DMSO (1.7 [mu]L) and varying concentrations of JNK or MKK inhibitors in DMSO. Cultured cells were harvested after 1 week of culture and analyzed by FACS staining.

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Abstract

The present invention provides methods of modulating mammalian, particularly human, stem cell and progenitor cell differentiation to regulate and control the differentiation and maturation of these cells along specific cell and tissue lineages. The methods of the invention relate to the use of certain small organic molecules to modulate the differentiation of stem cell populations along specific cell and tissue lineages, particularly embryonic-like stem cells originating from a postpartum placenta or stem cells isolated form sources such as cord blood. The invention also relates to the treatment or prevention of myelodysplastic syndrome or myeloproliferative syndrome, or symptoms thereof, comprising administration of JNK or MKK inhibitors, alone or in combination, as well as with or without the use of unconditioned cells or cells conditioned in accordance with other aspects of the invention. Finally, the invention relates to the use of such differentiated stem cells in transplantation and other medical treatments.

Description

[0001] This application claims the benefit of US Provisional Application No. 60 / 384,250, filed May 30, 2002, and US Provisional Application No. 60 / 434,833, filed December 19, 2002, each of which is hereby incorporated by reference in its entirety. [0002] 1 Introduction [0003] The present invention relates to methods of modulating mammalian stem and progenitor cell differentiation comprising exposing stem or progenitor cells to compounds that inhibit the activity of c-Jun N-terminal kinase (JNK) or mitogen-activated protein kinase kinase (MKK). The methods of the invention are used to regulate or control the differentiation or maturation of mammalian, especially human, stem cells along specific cell and tissue lineages. The methods of the invention involve the use of certain small organic molecules to modulate the differentiation of stem cell populations along specific cell and tissue lineages, and in particular the differentiation of embryonic-like stem cells derived from th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/403A61K31/416A61K31/423A61K31/428A61K31/48A61K31/505A61K35/12A61K35/14A61K35/26A61K35/44A61K45/00A61K48/00A61P7/06A61P35/02A61P43/00C12N5/074C12N5/0789
CPCC12N2501/125A61K2035/124C12N2501/70A61K31/00C12N2501/23A61K31/416A61K31/505C12N2501/22A61K31/423C12N5/0607C12N5/0647A61K31/428A61K31/403A61P7/06A61P35/02A61P43/00A61K31/42C12N5/00C12N5/0606
Inventor R·J·哈里里D·I·斯蒂尔林J·B·泽尔迪斯
Owner CELGENE CORP
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