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Inhibitor of stem cell proliferation and uses thereof

A stem cell and sequence technology, applied in the directions of cytokines/lymphokines/interferons, applications, growth factors/inducing factors, etc., can solve the problems of increased infection rate, low frequency of stem cells, and high susceptibility

Inactive Publication Date: 2007-07-25
WELLSTAT THERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] There are several limitations in introducing genes into human hematopoietic cells using retroviral vectors or gene transfer physical techniques: (1) The frequency of stem cells in hematopoietic tissues is low, and efficient gene transfer technology must be developed; (2) Stem cells with shorter cycles The higher the susceptibility to the vector, but the increased infection rate by stimulating stem cell proliferation with growth factors has the opposite effect on long-term gene expression
Because, cells containing the transgene are forced to undergo irreversible differentiation and lose their ability to self-renew

Method used

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  • Inhibitor of stem cell proliferation and uses thereof
  • Inhibitor of stem cell proliferation and uses thereof
  • Inhibitor of stem cell proliferation and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] Example 1: In vivo stem cell proliferation inhibition analysis

[0155] To measure the proliferation of stem cells, the 3 The H-TdR "suicide method" measures the number of CFU-S in the S phase of the cell cycle (Becker et al., Blood 26:296-308, 1965).

[0156] Immature hematopoietic progenitors-spleen colony-forming units (CFU-S) can be detected in vivo by macroscopic colonies formed in the spleens of lethally irradiated mice 8–12 days after intravenous injection of hematopoietic cells (Till & McCulloch 1961).

[0157] For standard CFU-S proliferation assays, usually using 3 H-TdR "suicide method" (Becker et al., 1965). The method is based on radiolabeled thymine ( 3 H-TdR) is incorporated into cells as a synthetic DNA precursor. CFU-S in the S phase of the cell cycle at the time of detection were killed by high radioactivity and thus failed to form colonies in the spleen. Then, by injecting with 3 Cell samples co-cultured with H-TdR and without 3 The differenc...

Embodiment 2

[0176] Example 2 In vitro stem cell proliferation inhibition analysis

[0177] The direct effect of INPROL was shown using the following assay system (Lord et al., The Inhibitors of Hematopoiesis, pp. 227-239, 1987). Multilineage factor (IL-3) dependent cell line FDCP mix A 4 (A 4 ), maintained in IMDM medium containing 20% ​​horse serum and 10% WEHI-3 conditioned medium as a source of colony-stimulating IL-3.

[0178] use 3 Proliferation detected by H-TdR incorporation assay: A 4 cells (5×10 4 In 100 μl medium containing 20% ​​horse serum and 50% WEHI-3 conditioned culture supernatant) at 37°C, 5% CO 2 Incubate for 16 hours.

[0179] Begin adding INPROL or crude BME (bone marrow extract) (component IV), then add to each group 3 H-TdR (3.7KBq in 50μl at 740GBq / mmol) was cultured for another 3 hours. Proliferation rates were determined by harvesting cells and calculating percent inhibition using the following formula.

[0180]

[0181] FDCPmix-A grown in the prese...

Embodiment 3

[0182] Example 3 In vivo injection of INPROL results in inhibition of CFU-S proliferation: dose and effect duration

[0183] In vivo injection of INPROL showed that INPROL can effectively block the recruitment of CFU-S into the cell cycle. Thus, these cells are protected from the cytotoxic effects of further treatment. Show its clinical potential application value.

[0184] The purpose of this experimental protocol was twofold: to examine the effect of INPROL on CFU-S when injected in vivo and to determine the effective duration of INPROL activity involved in cell cycle stem cells.

[0185] To stimulate CFU-S proliferation, according to the effects mentioned in Example 1, testosterone propionate (TSP) was injected.

[0186] BDF at day 0 1 The mice were injected with TSP (10mg / 100g), and 24 hours later, the mice in each experimental group (4 mice / group) were intraperitoneally injected with pINPROL 0μg, 5μg, 10μg and 15μg / mouse.

[0187] 24 hours after pINPROL injection,...

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Abstract

Disclosed and claimed are methods for the isolation and use of stem cell inhibiting factors for regulating the abnormal stem cell cycle and for accelerating the post-chemotherapy peripheral blood cell recovery. Also disclosed and claimed are the inhibitors of stem cell proliferation.

Description

field of invention [0001] The present invention relates to the use of inhibitors of stem cell proliferation that regulate the stem cell cycle in the treatment of humans or animals suffering from autoimmune diseases, aging, cancer, myeloid dysplasia, preleukemia, leukemia, psoriasis or other diseases involving hyperproliferative conditions . The invention also relates to methods of treatment of humans or animals that have been previously or have been exposed to chemotherapeutic drugs, other drugs that are damaging to stem cells that have entered the cell cycle, or radiation. Finally, the present invention relates to improvements in the maintenance or expansion of stem cells for autologous and allogeneic transplantation methods or for gene transfer. Background of the invention [0002] Most terminal cells in the regeneration system are short-lived and are constantly replaced during life. For example, blood cells are derived from multipotent hematopoietic stem cells (HSCs) wi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/00A61K45/00A61K35/14A61K35/28A61K35/44A61K38/00A61K38/02A61K38/04A61K38/12A61K38/16A61K38/21A61K38/22A61K38/41A61K38/42A61K39/00A61K39/39A61K48/00A61N5/00A61P5/00A61P17/06A61P19/08A61P31/12A61P35/00A61P35/02A61P37/00A61P37/06A61P41/00A61P43/00C07KC07K2/00C07K5/107C07K7/06C07K7/08C07K7/50C07K7/64C07K14/47C07K14/475C07K14/52C07K14/795C07K14/805C12N5/0789C12N5/10C12N15/00C12N15/09H04M11/00H04M11/04
CPCC07K14/4703C07K14/805A61K38/42H04M11/04C07K14/475H04M11/002C07K14/52A61K39/39A61P17/06A61P19/08A61P31/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P37/06A61P41/00A61P43/00A61P5/00A61K2300/00
Inventor V·科兹洛夫I·楚尔洛娃S·D·沃尔帕
Owner WELLSTAT THERAPEUTICS CORP
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