Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
1998-02-06
2001-07-17
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S003000, C800S018000, C800S025000
Reexamination Certificate
active
06262335
ABSTRACT:
TECHNICAL FIELD
The invention relates to transgenic animals with a progressive neurologic disease resembling Alzheimer's disease.
BACKGROUND
Alzheimer's disease (AD) is a progressive, fatal neurode generative disorder of the elderly. AD shows a slowly progressive mental deterioration with failure of memory, disorientation and confusion leading to profound dementia. There are several histologic features, but two are striking. First, argyrophilic plaques comprised of the amyloidogenic A&bgr; fragment of amyloid precursor protein (APP) are scattered throughout the cerebral cortex and hippocampus. Second, neurofibrillary tangles are found in pyramidal neurons predominantly located in the neocortex, hippocampus, and nucleus basalis of Meynert. There are other changes, also. Granulo-vacuolar degeneration in the pyramidal cells of the hippocampus has been considered by some to be more specific for AD than plaques or neurofibrillary tangles. Finally, there is neuronal loss and gliosis in the cerebral cortex and hippocampus.
There are patients with dementia who lack the pathologic features of AD (and by definition have a different disease), and conversely, there are individuals with many of the pathologic features of AD who were not demented prior to death. The diagnosis of AD requires that both the clinical and the pathological features characteristic for the disease be present in the patient; the diagnosis cannot be made with certainty from either clinical or pathological features alone. Whether neural dysfunction and clinical abnormalities precede the development of these pathologic features, particularly the amyloid plaques and neurofibrillary tangles, is unknown.
The clinical manifestations of AD predict the regions of affected brain structures in the forebrain, including the cerebral cortex, hippocampus, amygdala, and parahippocampal gyri. These regions are known as the cortico-limbic areas of the brain. The basal ganglia is spared, as is the hindbrain, including the cerebellum, the pontine and the medullary nuclei. Within the cerebral neocortex, the primary cortical areas area relatively spared, which corresponds to the relative clinical sparing of basic motor and sensory cortical functions.
Transgenic mice harboring APP transgenes have been described; however, transgene product expression falls considerably short of endogenous levels of APP (total APP levels in the other transgenic mice have not exceeded 150% of endogenous levels), and fails to generate a disease phenotype with a progressive neurobehavioral disorder accompanied by pathology in the cortico-limbic regions of the brain. In these other transgenic mice, there have been no signs of a progressive neurologic disorder or of neuropathologic changes in the brain which may be regarded as evidence of a true neurologic disease.
Preamyloid APP plaques have been observed in some transgenic mice. However, preamyloid APP plaques are not necessarily indicative of a disease, since they are routinely observed in human brain regions, such as the cerebellum, which are devoid of other signs of pathology or clinical manifestations. Increased APP immunoreactivity located within vesicular structures in hippocampal neurons of transgenic mice has been reported, but the significance of this immunoreactivity is unclear since the mice exhibited neither a progressive neurobehavioral disorder nor evidence of true neuropathology.
It therefore is of interest to develop a transgenic nonhuman mammalian model for AD wherein the animal develops a progressive neurologic disease of the cortico-limbic brain resembling AD, both clinically and pathologically (e.g. the gliosis and the specific brain regions affected). It also is desirable that the animal develops neurologic disease within a fairly short period of time from birth, facilitating the analysis of multigenerational pedigrees. The model can be used to study the pathogenesis and treatment of AD since there is a distinct and robust clinical and pathologic phenotype to examine and score.
Relevant Literature
Quon et al. (1991)
Nature
352:239 describe transgenic mice containing human amyloid precursor protein genes. Lamb et al. (1993)
Nature Genetics
5:22 describe transgenic mice in which the amount of amyloid precursor protein expressed is approximately 50% over endogenous levels.
Other transgenic mouse studies of Alzheimer amyloid precursor (APP) protein include the following. Greenberg, B. D. (1993) Abstract 421.12
, Society for Neuroscience Abstracts
19:1035. The APP protein gene was expressed using mAPP and mMt-I promoters. Schwartz, D. A. et al. (1993) disclose neuron-specific expression of human beta-amyloid precursor protein (APP) in transgenic mice. Abstract 421.13
, Society for Neuroscience Abstracts
19:1035. Savage, F. A. et al. (1993) disclose human amyloid precursor protein expression in transgenic mice as a model of Alzheimer's disease: search for pathology. Abstract 421.14
, Society for Neuroscience Abstracts
19:1035. Lieberburg, I. (1993) disclose expression of human protein in transgenic mice using the NSE promotor. Abstract 421.15
, Society for Neuroscience Abstracts
19:1035. Fukuchi, K. et al. (1993) disclose intestinal beta-amyloidosis in transgenic mice. Abstract 421.16, Society for
Neuroscience Abstracts
19:1035. A chicken beta-actin promotor and CMV enhancer were used for expressing the APP protein gene.
Wagner et al. (1981)
P.N.A.S. U.S.A
. 78:5016 describe transgenic mice containing human globin genes. Scott et al. (1989)
Cell
59:847 describe transgenic mice containing hamster prion protein genes. Hsiao et al. (1990)
Science
250:1587 describe transgenic mice containing mutant human prion protein genes. Hsiao disclosed a model for Gerstmann-Straussler-Scheinker disease (GSS), a rate neurodegenerative disease caused by mutations in the prion protein (PrP) gene, in transgenic mice in which levels of mutant transgene product exceeding endogenous levels were needed to generate a clinical and pathological phenotype (Hsiao et al., 1991; Hsiao, et al., 1993).
SUMMARY OF THE INVENTION
A transgenic non-human animal model for Alzheimer's disease is provided, together with methods and compositions for preparation of the animal model and methods for using it. The non-human mammals are obtained by the steps of introducing multiple copies of an expression cassette into the non-human mammal at an embryonic stage, and developing the embryo to term in a pseudo-pregnant foster female. The expression cassette comprises an amyloid precursor protein coding sequence operably joined to regulatory sequences for expression of the coding sequence in neurologic tissues at a level at least two to four-fold that of endogenous levels of wild-type amyloid precursor protein. The resulting transgenic non-human mammals develop progressive neurologic disease in the cortico-limbic areas of the brain. The transgenic animals find use for example in screening protocols for treatment and prevention of Alzheimer's disease.
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Lannfelt et al., “Alzheimer's disease: molecular genetics and transgenic animals models”,Behavioural Brain Research,57 (1993), pp. 207-213.
Felsenstein et al., Alz. and Parkin. Diseases, ed., I. Hanin et al., Plenum Press, New York, NY, pp. 401-409 (1995).
Moran et al. “Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human &bgr;-amyloid precursor protein”,Proc. Natl. Acad. Sci. USA,vol. 92, Jun. 1995,
Borchelt David R.
Hsiao Karen
Sisodia Sangram S.
Crouch Deborah
Fish & Richardson P.C.
Johns Hopkins University
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