Knockin mouse with a disruption in a PXR gene expressing human PXR
The present invention relates to transgenic non-human animals, tissues or cells derived therefrom and methods of producing them. The transgenic non-human animals or tissues or cells derived therefrom provide a system capable of expressing human proteins responsible for drug metabolism in place of the homologous endogenous non-human animal proteins and for the controlled expression of human genes introduced into the animal so that the expression of the human genes is regulated in a manner more closely analogous to that seen in vivo in humans. One aspect of the invention relates to the use of a human DNA sequence comprising at least part of introns 6 and/or 7 of the human PXR gene.
1. A transgenic mouse, or tissue or cells derived therefrom, whose genome comprises:
(i) an annulled pregnane X receptor transcription factor (PXR) gene; and
(ii) a DNA sequence encoding a human PXR gene knocked-into the mouse PXR locus, wherein:
a. said DNA sequence has an intron-exon structure and comprises at least part of intron 6 and/or intron 7 of the human PXR gene; and
b. expression of the human PXR gene is under the control of a mouse PXR promoter.
2. The transgenic mouse, or tissue or cells derived therefrom according to claim 1 , wherein said human DNA sequence comprises at least part of introns 4, 5, 6, and/or 7 of the human PXR gene.
3. The transgenic mouse, or tissue or cells derived therefrom according to claim 1 , wherein said DNA sequence comprises introns 4-8 of the human PXR gene.
4. The transgenic mouse, or tissue or cells derived therefrom according to claim 1 , wherein said DNA sequence further comprises at least part of introns 2, 3, 6, 7, and/or 8 of the human PXR gene.
5. The transgenic mouse, or tissue or cells derived therefrom according to claim 1 , wherein said human DNA sequence comprises introns 2-8 of the human PXR gene.
6. The transgenic mouse, or tissue or cells derived therefrom according to claim 1 , wherein said human DNA sequence comprises a sequence that is at least 70% identical to the sequence of SEQ ID NO:2 or the sequence of SEQ ID NO:3.