Prion gene modified mouse which exhibits heart anomalies

Details Prion gene modified mouse which exhibits heart anomalies Prion gene modified mouse which exhibits heart anomalies

2001-01-25

2003-12-02

Crouch, Deborah (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Nonhuman animal

Transgenic nonhuman animal

C800S003000, C800S008000, C800S013000, C800S021000, C800S025000, C435S455000, C435S463000, C435S325000, C435S320100

Reexamination Certificate

active

06657105

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method for detecting an aberrant animal-derived prion gene. The invention further relates to a prion gene modified mouse which exhibits heart anomalies, and to a method for detecting drugs which reduce anomalies in an electrocardiogram of said mouse.
PRIOR ART
Transmissible spongiform encephalopathy is a neurodegenerative disease observed in many kinds of mammal. These diseases are prion diseases caused by anomalies in prion proteins (PrP). Among these, kuru, Creutzfeldt-Jacob disease (CJD), Gerstmann-Straussler-Scheinker desease (GSS) in humans; and scrapie and bovine spongiform encephalopathy in ruminant livestocks such as sheep and cattle are known, and are a serious problems even today. A cause of the epidemic of prion diseases such as BSE in animals is thought to be livestock feed from sheep infected with scrapie, however, the causal link between the feed and incidence has not been confirmed.
The British medical journal “Lancet” issued on Apr. 6, 1996 reported 10 cases of human transmissible spongiform encephalopathy, a new type of Creutzfeldt-Jacob disease (CJD) in the United Kingdom. This disease has been on the increase having killed 48 persons in the United Kingdom and 2 persons in France; and CJD has been under surveillance all over the world including Japan. The World Health Organization (WHO) has promoted research and development using transgenic animals. They are considered to be useful for detecting diseases sensitively in early stages and developing removal methods of pathogens. Owing to this research, the causal link between mad cow disease and CJD is gradually being elucidated.
At present, in Prusiner's report (S. Prusiner et al. PNAS 96:15137-15192, 1999) a bovine prion gene modified mouse is presented; and each pathogen, BSE, scrapie and CJD is said to appear at around 200 days in this transgenic mouse. Accordingly, the transgenic mouse indicates the high possibility that these three pathogens are identical. On the other hand, in Collinge's report (J. Collinge et al. PNAS, 91:9936-9940, 1994), a human prion gene modified mouse was presented; and CJD is said to appear at around 220 days in this mouse. However, a mouse in which the incubation period has been shortened using various animal-derived prion genes, is not yet known.
It is of great interest to note the fact that a wild ruminant such as kudu and oryx has a shorter incubation period compared with that of livestock ruminants such as sheep and cattle; and their progress after incidence is rapid. For example, it has been reported that generally the incubation period in sheep is 36-48 months and incidence is at age 36-48 months, and in cattle the incubation period is 36-72 months and the incidence is at age 60-80 months, but on the other hand, in Oryx demmah the incubation period is 21 months and incidence is at age 30 months. This indicates that the difference of transmissibility of spongiform encephalopathy and the incubation period might depend on the difference of amino acid sequence of each PrP. Up to now, the gene encoding a prion protein has been identified in many mammals such as human, sheep, cattle, mouse, hamster, etc; and it is known that their genes show not less than 90% amino acid homology to each other and they are highly conserved (N. Oesch et al., Cell, 40, 735 (1985); D. Westaway et al., Proc. Nat. Acad. Sci. USA 91: 6418-6422 (1994); D. Westaway et al., Genes and Develop. 8:959-969 (1994); N. Hunter et al., J. Gen. Virol. 74 1025-1031 (1993)).
Now the system for rapidly detecting the scrapie pathogen is required to be established. Human or bovine prion gene modified transgenic mice have not yet been provided sufficiently in the world; therefore under present circumstances, the pathogen is detected by inoculating the animal tissues of interest in the brain of an ordinary CD-1 mouse (CLEA JAPAN). In the case of inoculating sheep brain tissue with this method, at least 300 days are required for the detection. Establishing a method for detecting the aberrant prion gene within a shortened incubation period before prion disease incidence may overcome the disadvantage of detection by the present bioassay which has high sensitivity but lacks rapidness.
On the other hand, a heart disease model in mouse is rare. Although the transgenic mouse with familial amyloid polyneuropathy has been reported, there is no report of a transgenic mouse as a heart specific disease model. The prion gene modified mouse with heart specific disease may also be useful for developing pharmaceuticals for heart diseases and studies on life-style related diseases.
The object of the present invention is to provide a method for detecting an aberrant animal-derived prion gene.
The present inventors have studied extensively and intensively to solve the above problems and have now found that a prion gene modified mouse exhibits heart disease when a foreign prion gene is aberrant, thereby completing the invention.
Furthermore, in the past, there was no report which confirms abnormal electrocardiogram wave profiles and abnormal tissues in the heart of a mouse which overexpresses mouse normal prion genes (m-Prnp) (
Prion and Prion Disease,
Jun Tateishi. KYORITSU SHUPPAN, p23 (1998)).
SUMMARY OF THE INVENTION
The present invention relates to a method for detecting an aberrant animal-derived prion gene in which the prion gene is determined to be aberrant when the prion gene modified mouse exhibits heart disease.
The invention further relates to a prion gene modified mouse which exhibits heart disease.
Still further, the invention relates to a method for detecting drugs which reduce abnormal waves in an electrocardiogram of the prion gene modified mouse.
The invention will be described in detail as follows.


REFERENCES:
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M. Poidinger et al., “Sequence Analysis of the PrP protein from two species of antelope susceptible to transmissible spongiform encephalopathy,”Arch. Virol., 131: 193-99 (1993).
A.R. Austin et al., “Abnormalities of the heart and rhythm in bovine spongiform encephalopathy,”Veterinary Record, 141: 352-7 (1997).
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Hunter, N. et al., “Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie,”J. Gen Vir., 74: 1025-31 (1993).
Oesch, B. et al., “A cellular gene encodes scrapie PrP 27-30 protein,

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