Transgenic rabbit that expresses a functional human lipoprotein (a)
AssigneeAventis Pharmaceuticals Inc.
InventorsDidier Rouy, Nicolas Duverger, Florence Emmanuel, Patrice Denefle, Louis-Marie Houdebine, Celine Viglietta, Edward M. Rubin, Steven D. Hughes
Life of this patent
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Abstract
A transgenic rabbit which has in its genomic DNA sequences that encode apolipoprotein (a) and apolipoprotein B polypeptides which are capable of combining to produce lipoprotein (a), a process for creating such a rabbit, and the use of the rabbit to identify compounds which are effective in the treatment of human diseases which are associated with, induced and/or exacerbated by Lp(a) expression.
Claims22
A transgenic rabbit whose genome comprises a first nucleic acid sequence, which encodes a human apolipoprotein (a) polypeptide, and a second nucleic acid sequence, which encodes a human apolipoprotein B polypeptide, said first and second nucleic acid sequences being operatively associated with a first and second promoter region, respectively, for functional transcription such that said human apolipoprotein (a) and human apolipoprotein B polypeptides are expressed in such a manner that they combine in vivo in said transgenic rabbit to produce human lipoprotein (a).
A process for making a transgenic rabbit which is capable of producing human lipoprotein (a) comprising mating a first rabbit which has a genome comprising a first nucleic acid sequence encoding a human apolipoprotein (a) polypeptide and is capable of expressing human apolipoprotein (a) with a second rabbit which has a genome comprising a second nucleic acid sequence encoding a human apolipoprotein B polypeptide and is capable of expressing human apolipoprotein B, said first and second nucleic acid sequences being operatively associated with a first and second promoter region, respectively, for functional transcription such that said human apolipoprotein (a) and human apolipoprotein B polypeptides are expressed in such a manner that they combine in vivo in said transgenic rabbit to produce human lipoprotein (a).
A method for determining whether a compound can treat atherosclerosis or an undesirable lipid profile comprising:
- comparing the lipid profile or state of atherosclerosis in a first transgenic rabbit fed a cholesterol-rich diet and treated with said compound, to the lipid profile or state of atherosclerosis in a second transgenic rabbit fed a cholesterol-rich diet but not treated with said compound;
- and
- determining the potential therapeutic effect of said compound based upon comparative evaluation of the lipid profile or state of atherosclerosis in said first and second transgenic rabbits;
- wherein said first and second transgenic rabbits are capable of producing human lipoprotein (a), develop human-like atherosclerotic lesions when fed a cholesterol-rich diet, and have within their genomic DNA sequences which encode human apolipoprotein (a) and human apolipoprotein B polypeptides, said sequences being operatively associated with a first and second promoter region, respectively, such that said human apolipoprotein (a) and human apolipoprotein B polypeptides are expressed in such a mamer that they combine in vivo in said transgenic rabbits to produce human lipoprotein (a).
A method for determining whether a compound can inhibit assembly of a human lipoprotein (a) particle comprising comparing the level of human lipoprotein (a) production in a first transgenic rabbit which has been treated with said compound and which is capable of producing human lipoprotein (a) to the level of production of human lipoprotein (a) in a second transgenic rabbit that has not been treated with said compound and which is capable of producing human lipoprotein (a), said first and second transgenic rabbits each having within their genomic DNA sequences which encode human apolipoprotein (a) and human apolipoprotein B polypeptides, said sequences being operatively associated with a first and second promoter region, respectively, such that said human apolipoprotein (a) and human apolipoprotein B polypeptides are expressed in such a manner that they combine in vivo in said transgenic rabbits to produce human lipoprotein (a).
A transgenic rabbit whose genome comprises a first nucleic acid sequence, which encodes a human apolipoprotein (a) polypeptide, and a second nucleic acid sequence, which encodes a human apolipoprotein B polypeptide, said first and second nucleic acid sequences being operatively associated with a first and second promoter region, respectively, for functional transcription such that apolipoprotein (a) polypeptide plasma level is stable throughout the sexual maturity of said rabbit and about 80% of said apolipoprotein (a) polypeptide is covalently bound to human apolipoprotein B or rabbit apolipoprotein B.
A transgenic rabbit whose genome comprises a first nucleic acid sequence, which encodes a human apolipoprotein (a) polypeptide, and a second nucleic acid sequence, which encodes a human apolipoprotein B polypeptide, said first and second nucleic acid sequences being operatively associated with their respective natural promoter regions for functional transcription such that said human apolipoprotein (a) and human apolipoprotein B polypeptides combine in vivo in said transgenic rabbit to produce human lipoprotein (a).
A process for making a transgenic rabbit which is capable of producing human lipoprotein (a) comprising mating a first rabbit which has a genome comprising a first nucleic acid sequence encoding a human apolipoprotein (a) polypeptide and is capable of expressing human apolipoprotein (a) with a second rabbit which has a genome comprising a second nucleic acid sequence encoding a human apolipoprotein B polypeptide and is capable of expressing human apolipoprotein B, said first and second nucleic acid sequences being operatively associated with their respective natural promoter regions for functional transcription such that said human apolipoprotein (a) and human apolipoprotein B polypeptides combine in vivo in said transgenic rabbit to produce human lipoprotein (a).
Dependencies are inferred from the claim text.