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Transgenic non-human mammals as models for human pathologies of stem cell origin

a human pathology and stem cell technology, applied in the field of transgenic non-human mammals, can solve the problem of not specifically reproducing human pathologies, and achieve the effects of suppressing or increasing the natural course of each pathology, predicting the efficacy, and increasing the tendency to develop

Inactive Publication Date: 2006-06-15
UNIV DE SALAMANCA OTRI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a solution for developing animal models that reproduce human pathology of stem cell origin. By using a DNA construct that includes a gene controlled by a promoter that directs expression in Sca-1+ cells, transgenic mammals can be generated that show varying levels of human pathology. These animal models can be used for studying how the pathology develops, predicting the efficacy of therapies, discovering new therapies, and identifying alleles that influence the natural course of the pathology. The invention also includes a transgenic non-human mammal that contains a transgene and its progeny, as well as a procedure for preparing a transgenic non-human mammal. The use of a promoter that directs expression in Sca-1+ cells and the use of a promoter that directs expression in Sca-1+ cells as a vehicle of therapeutic strategies are also objects of the invention.

Problems solved by technology

However, said models have only shown that the proteins expressed by said genes or gene fusions are tumorigenic, but they have not specifically reproduced the human pathology with which they are associated.

Method used

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  • Transgenic non-human mammals as models for human pathologies of stem cell origin
  • Transgenic non-human mammals as models for human pathologies of stem cell origin
  • Transgenic non-human mammals as models for human pathologies of stem cell origin

Examples

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example 1

Generation of Transgenic Mice

[0095] 1.1 Generation of Sca-1+ BCR-ABLp210 transgenic mice

[0096] In order to examine the direct consequences of the expression of the gene product BCR-ABLP210 (gene fusion that results as a consequence of the t(9:22)(q34;q11) and that is associated with chronic myeloid leukemia) in vivo, the cDNA of the chimeric human protein BCR-ABLP210 was cloned under the control of the promoter pLy-6E.1 of mouse and the fertilized oocytes were injected into C57BL / 6J×CBA mice following the technique described previously in the section on the “Methods”. Two transgenic founder mice (Sca-1+ BCR-ABLP210) showed a capacity to transmit the transgene down the germ cell line. The expression of the transgene was observed in both lines and the progeny multiplied up to level F7 (generation 7). The expression of the transgene was demonstrated by PCR and / or Western blot analysis. Both cell lines showed preferential expression in Sca-1+ cells. The expression of the transgene was...

example 2

Production of Leukemias in Transgenic Mice

[0106] Although in human pathology, the chimeric products of the genes Sca-1+ BCR-ABLp210, Sca-1+ BCR-ABLp190, Sca-1+ Slug, Sca-1+ Snail, Sca-1+ HOX11, Sca-1+ RHOM2 / LMO-2 and Sca-1+ TAL1 are associated with different types of leukemia, specifically, with chronic myeloid leukemia (BCR-ABLP210), B-cell acute lymphoblastic leukemia (BCR-ABLp190) and T-cell acute lymphoblastic leukemias (HOX11, RHOM2 / LMO-2 and TAL1), the current murine models for said leukemias have failed when it comes to reproducing said pathologies consistently [Annu. Rev. Genetics (1997) 31:429-453; Current Genomics (2000), 1: 71-80] due to the difficulty of choosing a promoter for manipulating the expression of the appropriate cell type.

[0107] The detailed analysis of the leukemia cells of different transgenic mice tested (Sca-1+ BCR-ABLP210 (FIGS. 1 and 2), Sca-1+ BCR-ABLp190 (FIG. 3), Sca-1+ HOX11, Sca-1+ RHOM2 / LMO-2 and Sca-1+ TAL1) allowing diagnosis of the correspond...

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Abstract

Transgenic non-human mammals that reproduce human pathologies of stem cell origins, such as chromosomal anomalies associated with chronic myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute or lymphoblastic leukemia, or with the migration of hematopoietic or embryonic stem cells. The transgenic non-human mammals can be produced using as a strategy the expression of genes involved in said pathologies by means of a promoter that directs the expression of a transgene in Sca-1+ cells. Said transgenic animals constitute a model for the study of said diseases and for the evaluation of compounds for the treatment and / or prevention of the diseases. Also disclosed are DNA construct and methods useful for producing the non-human transgenic mammals.

Description

FIELD OF THE INVENTION [0001] The invention relates to transgenic non-human mammals that reproduce human pathologies of stem cell origins using, as a strategy, expression of genes involved in said pathologies in human beings by means of a promoter that directs expression of a transgene in Sca-1 cells. BACKGROUND OF THE INVENTION [0002] Transgenic animals are animals that carry an exogenous gene (transgene) in their genome, said gene having been introduced into germ cells of the animal, or into a predecessor thereof, at an early stage of development. The introduction of a transgene into the animal may have the aim of studying the behavior, expression or function of the gene introduced. Alternatively, the aim could be to genetically improve the affected individual for therapeutic ends or to improve the animal. [0003] The generation of transgenic mammals is well established (see for example, Hogan, Constantini & Lacy (1986), “Manipulating the Mouse Embryo. A Laboratory Manual”, Cold Sp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01K67/027C12N5/06C12N15/87A61K31/7088A61K31/7105A61K31/711A61K35/76A61K48/00A61K49/00A61P7/00A61P35/00A61P35/02C07K14/82C12N5/10C12N15/09C12N15/12C12N15/85
CPCA01K67/0271A01K67/0275A01K2217/05A01K2227/105A01K2267/03A01K2267/0331A01K2267/0381A61K49/0008C07K14/82C12N15/8509C12N2830/008G01N33/5011A61P35/00A61P35/02A61P43/00A61P7/00
Inventor GARCIA, ISIDRO SANCHEZLOSADA, JESUS PEREZ
Owner UNIV DE SALAMANCA OTRI
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