Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Patent
1994-10-24
1998-07-07
Stanton, Brian R.
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
424 91, 424 92, 435 4, 4351723, 935 13, 935 34, 935 52, 935 70, A61K 4900, C12N 500, C12N 1511, C12Q 100
Patent
active
057771936
DESCRIPTION:
BRIEF SUMMARY
This invention relates to animals having specifically designed alterations in pre-existing endogenous genetic loci, eg. animals having targeted disruptions of specific genes. In particular, the invention relates to animals in which the gene for a colony-stimulating factor is disrupted so as to create a null allele, whereby the animal does not express any detectable colony-stimulating factor. The colony-stimulating factor is granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor. In a preferred embodiment of the invention, the animal is a rodent such as a mouse.
BACKGROUND OF THE INVENTION
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic growth factor which in vitro stimulates the survival, proliferation, differentiation and function of myeloid cells and their precursors, particularly neutrophil and eosinophil granulocytes and monocyte/macrophages (for review, see 1). The In vivo effects of GM-CSF have been studied in murine models by injecting pharmacological doses of GM-CSF (2), by generating GM-CSF transgenic mice (3), and by reconstituting lethally irradiated mice with bone marrow cells overproducing GM-CSF (4).
These studies confirm the haematopoietic activity of GM-CSF in vivao, and suggest that excess levels of GM-CSF may be implicated in some disease processes. However, the usual physiological role of GM-CSF is not well defined (5). Endogenously-produced GM-CSF is not usually detectable in serum (6), and in humans altered serum levels have not correlated clearly with haematological or disease processes (1,6). It has been suggested that GM-CSF may be produced and act locally (1), but the cells producing GM-CSF in vivo have yet to be identified. Moreover, it is not clear whether GM-CSF is an essential regulator for steady-state production of granulocytes and macrophages, or whether it is required as a regulator for emergency haematopoiesis in response to challenges such as bacterial infection. It is also not known whether GM-CSF is involved in the normal development of non-haematopoietic tissues.
Granulocyte colony-stimulating factor (G-CSF) is a haematopoietic growth factor which in vitro controls granulopoiesis. It stimulates the survival, proliferation, differentiation and function primarily of neutrophil granulocytes. As in the case of GM-CSF, the in vivo effects of G-CSF have been studied in murine models by injection of pharmacological doses of G-CSF and by reconstitution of lethally irradiated mice with bone marrow cells transformed with a retroviral vector carrying cDNA encoding G-CSF (reviewed in Reference 7). However, as with GM-CSF, the usual physiological role in vivo of G-CSF is unclear. It may act as a regulator in steady-state granulopoiesis, or may function as a regulator for emergency granulopoiesis in response to specific challenges requiring increased neutrophil production, such as infection (7).
G-CSF and its isolation, characterisation, and recombinant production have been extensively reviewed, for example papers cited in References 5 and 7.
Until recently, genetic studies depended upon the discovery of random mutations (either spontaneous or induced) or of pre-existing genetic polymorphisms. However, following the rapid development of recombinant DNA technology and of identification of specific genes, particularly in mice, by analogy to genes from other species or from the biochemistry of the protein products which they encode, methods for specifically-targeted deletion or modification of genes have been developed. Provided that a cloned, genomic fragment of the chosen genetic locus is available, it is possible to generate null alleles by disruption of the gene, to modify functional properties of the gene such as transcriptional pattern, mRNA or protein maturation pattern, or to modify the ability of the protein to interact with other gene products. This is achieved by using conventional recombinant DNA methods to introduce the desired mutation into a cloned DNA sequence of the chosen gene; the mutation is then tr
REFERENCES:
Stedman's Medical Dictionary, 24th Ed. p. 1242.
Bradley, A. et al (1992) Biotechnology 10, 534-539.
Schorle, A. et al (1991) Nature 352, 621-624.
Lieschke, G.J. et al (1991) Clinical Oncology Society of Australia, Inc., Annual Scientific Meeting. Abstract Only.
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Stanley, E. et al (1985) The EMBO Journal 4, 2569-73.
Tsuchiya, M. et al (1987). Eur. J. Biochem 165, 7-12.
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Huffman, J.A. et al (1996). J. Clin. Invest. 97, 649-655.
Dunn Ashley Roger
Fowler Kerry J.
Grail Dianne
Lieschke Graham John
Stanley Edouard Guy
Ludwig Institute for Cancer Research
Stanton Brian R.
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