Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
2000-08-24
2003-02-04
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
86, 86, C435S029000, C435S320100, C435S354000, C536S023500
Reexamination Certificate
active
06515197
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to the field of neurobiology and more specifically to a mouse model of neurodegenerative disease.
The hereditary ataxias are a complex group of neurodegenerative disorders characterized by varying abnormalities of balance attributed to dysfunction or pathology of the cerebellum and cerebellar pathways. In many of these disorders, dysfunction or structural abnormalities extend beyond the cerebellum, and can involve basal ganglia function, oculo-motor disorders and neuropathy. The dominant spinocerebellar ataxias (SCAs) represent a heterogeneous group of disorders with a prevalence of familial cases of approximately 1 in 100,000.
A variety of genes and phenotypes have been identified to be associated with a family of neurodegenerative diseases, including SCA1, SCA2, Machado-Joseph disease (SCA3), SCA6, SCA7, Huntington disease, spinal bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. These diseases are associated with the expansion of a polyglutamine (polyQ) tract in the protein encoded by the respective disease genes.
Although the study of normal and diseased human brains can provide important insights into polyQ-associated disease pathogenesis, such observations are limited to the terminal stages of the disease process. Mouse models can circumvent this problem, but many mouse models of human polyQ diseases rely on the use of truncated constructs or very long polyQ tracts to produce neruodegeneration (Ikeda et al.,
Nature Genet
., 13:196-202 (1996); Mangiarini et al.,
Cell
, 87:493-506 (1996); Mangiarini et al.,
Nature Genet
., 15:197-200 (1997); Davies et al.,
Phil. Trans. R. Soc. Lond. B Biol. Sci
., 354:981-989 (1999)). In addition, several polyQ mouse models do not show prominent neuronal loss, a defining feature of human polyQ diseases.
Thus, there exists a need for a non-human animal model of polyQ neurodegenerative disease and methods of identifying therapeutic agents useful for treating neurodegenerative disease. The present invention satisfies this need and provides related advanatages as well.
SUMMARY OF THE INVENTION
The invention provides a transgenic non-human mammal comprising nucleated cells containing a transgene encoding an ataxin-2 polypeptide comprising a polyglutamine tract. In particular, the transgenic non-human mammal can be a mouse. The invention also provides methods of using a transgenic non-human mammal expressing an ataxin-2 polypeptide to identify a therapeutic agent for use in treating a neurodegenerative disease by administering a compound to a transgenic non-human mammal expressing an ataxin-2 polypeptide and screening the transgenic non-human mammal for an improved neurological response associated with a neurodegenerative phenotype of the transgenic non-human mammal, thereby identifying a therapeutic agent for use in treating the neurodegenerative disease.
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Huynh Duong P.
Pulst Stefan M.
Campbell & Flores LLP
Cedars-Sinai Medical Center
Crouch Deborah
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