Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Patent
1996-09-20
1998-08-11
Chambers, Jasemine C.
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
4351723, 424 91, 424 92, C12N 1500, A61K 4900
Patent
active
057929025
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. .sctn. 371 national application of PCT International Patent Application No. PCT/FR95/00318, filed Mar. 16, 1995, and claims priority pursuant to 35 U.S.C. .sctn. 119 of French patent application No. 94/103263, filed Mar. 21, 1994.
The present invention relates to a transgenic rabbit which expresses a protein which is capable of interfering in diseases which are linked to dyslipoproteinaemias, to the process for its preparation and to its use as an animal model.
Dyslipoproteinaemias are disorders in the metabolism of the lipoproteins which are responsible for transporting lipids such as cholesterol and triglycerides in the blood and the peripheral fluids. They lead to important diseases, such as, in particular, atherosclerosis, which diseases are linked, respectively, to hypercholesterolaemia, hypocholesterolaemia or hypertriglyceridaemia.
Atherosclerosis is a complex, polygenic disease which is defined, on the histological plane, by deposits (lipid or fibro-lipid plaques) of lipids and other blood derivatives in the wall of the large arteries (aorta, coronary arteries and carotid). These plaques, which are more or less calcified according to the progress of the disease, can be associated with lesions and are linked to the accumulation, in the arteries, of fatty deposits which essentially consist of cholesterol esters. These plaques are accompanied by a thickening of the arterial wall together with hypertrophy of the smooth muscle, the appearance of foam cells and the accumulation of fibrous tissue. The atheromatous plaque is very clearly raised on the wall, thereby conferring on it a stenosing character which is responsible for the vascular occlusions, by means of atheroma, thrombosis or embolism, which occur in the worst-affected patients. Hypercholesterolaemias can, therefore, lead to very serious cardiovascular diseases such as infarction, sudden death, cardiac decompensation, cerebrovascular diseases, etc.
It is particularly important, therefore, to have immediately available treatments which diminish, in some disease situations, the levels of plasma cholesterol or stimulate the efflux of cholesterol (reverse transport of cholesterol) from the peripheral tissues in order to unload the cells which have accumulated the cholesterol in the context of forming an atheroma plaque. (Cholesterol is transported in the blood by a variety of lipoproteins including the low density lipoproteins (LDL) and the high density lipoproteins (HDL). The LDLs are synthesized in the liver and are responsible for supplying the peripheral tissues with cholesterol. By contrast, the HDLs pick up cholesterol in the peripheral tissues and transport it to the liver where it is stored and/or broken down).
From this point of view, it would be worthwhile to have available an animal model which was capable of expressing a protein which was able to interfere in the diseases which are linked to dyslipoproteinaemias. Such an animal model would be particularly advantageous for understanding these diseases and, more specifically, the regulatory mechanisms which they initiate. It would make it possible to test, rapidly and in vivo, a considerable number of therapeutic agents for the purpose of detecting a potential activity associated with the expression of the said proteins. Furthermore, such a model would be of interest for developing novel therapeutic methods for treating this type of disease, such as methods which are based on gene therapy, for example.
The specific object of the present invention is to propose a rabbit which has been genetically modified in this sense.
Generally speaking, the murines, namely mice, rats and guinea pigs, are the most widely used animal models. They are easy to manipulate and inexpensive. Unfortunately, these small mammals are not always compatible with the intended application. Thus, they are not always representative of the human model and its metabolism. Closer to man, the chimpanzee is a test animal which is used, in particular, for detecting therapeutic agents and vaccine
REFERENCES:
Perevozchikov et al., Human APO A-1 cDNA Gene Expression in Transgenic Rabbits: Modeling of the Neurological Syndrome of Human Tangier Disease, Biological Abstracts, 96,3, Abst. No. 28308, (1993).
Chowdhury et al., Long-Term Improvement of Hypercholesterolemia After ex Vivo Gene Therapy in LDLR-Deficient Rabbits, Science, 254, 1802-1804, (1991).
Schultz et al., Protein Composition Determines the Anti-Atherogenic Properties of HDL in Transgenic Mice, Nature, 365, 6448, 762-764, (1993).
Latta et al., Human Alpolipoprotein AII Can Be Overproduced as A Recombinant Protein From E-coli, Circulation, 86, 4, 133, (1992).
Duverger et al., Functional Characterization of Human Recombinant Apolipoprotein AIV Produced in Escherichia coli, Euro. Journal of Biochemistry, 201, 2, 373-383, (1991).
Perevozchikov et al. Expression of Human Apolipoprotein A-1 gene cDNA in Transgenic Rabbits: Modeling of the Neurologic Syndrome of Human Tangier Disease. Molecular Biology, vol. 27, No. 1, pp. 6-14, Jan. 2, 1993.
Hoeg et al, Development of transgenic watanabe heritable hyperlipidemic rabbits expressing human apoA-1. Circulation, vol. 88, No. 4, part 2, #0010, Oct. 1993.
Benoit Patrick
Denefle Patrice
Duverger Nicolas
Houdebine Louis Marie
Chambers Jasemine C.
Clark Deborah J. R.
Rhone-Poulenc Rorer S.A.
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