Rodent model of prostate cancer

A technology for rodents and prostates, applied in animal cells, vertebrate cells, microorganisms, etc., can solve problems such as limiting correlations

CN108135151AInactive Publication Date: 2018-06-08REGENERON PHARM INC
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2018-06-08
Estimated Expiration
Not applicable · inactive patent

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Abstract

This disclosure provides a rodent model of prostate cancer. The rodents disclosed herein comprise a transgene that provides prostate-specific expression of an oncogenic protein (e.g, an SV40 tumor antigen) under the control of 5' and 3' regulatory regions of a mouse probasin gene. The rodents develop progressive forms of prostate tumor that resemble the development of human prostate cancer.
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Description

[0001] Cross References to Related Applications

[0002] This application claims the benefit of priority to US Provisional Application No. 62 / 213,389, filed September 2, 2015, the entire contents of which are incorporated herein by reference. field of invention

[0003] The present disclosure relates to a rodent model of prostate cancer. The rodents disclosed herein comprise a transgene comprising the SV40 tumor antigen coding sequence operably linked to the 5' and 3' regulatory regions of the mouse probasin gene. The rodents disclosed herein exhibit prostate-specific expression of the transgene and develop progressive forms of prostate tumors that mimic the development of human prostate cancer.

[0004] The sequence listing is incorporated by reference

[0005] The sequence listing is an ASCII text file named 32350_10161US01_SequenceListing.txt with a size of 440KB created on August 24, 2016, submitted to the US Patent and Trademark Office via EFS-Web, and incorporated here...

Examples

Embodiment 1

[0125] Example 1. Production of Luci-TRAMP mice

[0126] This example illustrates the generation of transgenic mice (also referred to herein as Luci-TRAMP mice) comprising a transgene comprising the nucleic acid coding sequence for the SV40 tumor antigen-T2A-luciferase polypeptide flanked by The 5' regulatory region and the 3' regulatory region of the mouse probasin gene.

[0127] through bacterial homologous recombination and technology to construct vectors containing transgenes (see for example U.S. 6,586,251 and Valenzuela et al., High-throughput engineering of the mousegenome coupled with high-resolution expression analysis, 2003, Nature Biotech. 21(6):652-659). Briefly, RP23-417B18 was cloned using a bacterial artificial chromosome (BAC) containing the mouse probasin gene and modified as follows. A fragment consisting of 75 base pairs (bp) of mouse 5'-UTR, SV40-T antigen (without stop codon), followed by T2A sequence, NcoI / XhoI / NheI restriction site and stop codon and ...

Embodiment 2

[0132] Example 2. Longitudinal analysis of the Luci-TRAMP cohort

[0133] Luci-TRAMP mice generated from ES clone A-C10(5x) were designated MAID 2319 and used in the experiments described in this example. A mouse named MAID 2363 containing the transgene "R26-L-luc2" at the Rosa 26 locus in the genome (which expresses a luciferase reporter in a non-tissue-specific manner) and wild-type mouse F1H4 were used as controls .

[0134] Cohorts of 35 MAID2319 mice (Luci-TRAMP) were bred to allow prostate tumor development, while an equal number of MAID 2363 mice (R26-L-Luc2) and F1H4 mice were bred. Five mice were removed from each group at 2, 4, 6, 8, 11 and 16 months for in vivo luciferase imaging, μCT scanning (to assess lean muscle / fat / bone mass), histopathology Physiological analysis (starting at 4 months) and molecular phenotyping (RNA-seq and qPCR).

[0135] For longitudinal studies, at each indicated time point (inset below), fluorescein (150 mg / kg PerkinElmer) was administe...