Engineered Biomarker models

CXR Biosciences has developed Engineered Biomarker models designed for the rapid assessment of potential toxic effects by determining the mechanism of induced toxicity.

A transcriptionally regulated 'stress' promoter from a gene involved in a pathway of toxicity is used to drive the expression of two reporter proteins, one of which is excreted into the blood and urine, and another that remains localised in the tissue in which the promoter is activated.  Any compound that causes induction of the stress promoter induces expression of both reporters, enabling the response to toxic agents to be determined in real time, non-invasively in the urine. At the end of the experiment the site of the toxic response is determined through histocytochemistry.To date CXR have developed transgenes to 8 different stress promoters that are associated with biochemical pathways involved in around 80% of the toxic responses to drugs.

Two types of reporter system have been generated.

• One is where the promoter of a stress-responsive gene has been linked to the beta galactosidase reporter. This allows the transcriptional change due to cytotoxic stress to be measured in vivo either single tissues or in the whole animal by lacZ staining.
• The other is the use of a promoter driving an excretable reporter, human chorionic gonadotrophin (hCG) beta chain, which is not biologically active but, on production in cells, is excreted in the blood stream and subsequently into the urine.

Benefits

This approach provides a means of studying the relationship between chemical exposure and toxic response in a time- and dose- dependent manner in a single mouse.  By engineering into mice early biomarkers for toxicity and, potentially carcingenicity, the models provide a non-invasive early biomarker system, where inter-animal variability will be reduced and effects will be observed prior to the onset of overt toxicity. Animal use will be significantly reduced

More Rapid

Usually compound toxicity is only observed after long term animal toxicity studies.  The toxicity reporter models can be used to determine potential toxicity within days of administration of compound.

More informative

The unique excreted reporter system facilitates determination of the mechanism of toxicity by identifying interaction of the test compound with biochemical pathways associated with commonly observed toxicities in real time.  The use of an in situ reporter system facilitates the determination of specific tissue toxicity by means of histopathology.

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