HUMANISED MOUSE MODELS

CXR Biosciences in collaboration with Artemis and ITI Lifesciences are developing a range of humanised mice that are more predictive of human drug metabolism and disposition.

Over 70% of potential drug compounds fail during development because of poor pharmacokinetic profiles, lack of efficacy, toxicity in preclinical studies or safety issues in clinical trials. These failures reveal an urgent need for more predictive pre-clinical models that identify unsuitable compounds earlier in the drug development process, and before valuable resources are wasted on compounds that are ultimately destined to fail.

Humanised mouse models incorporate human genes central to human pathways of drug bio-distribution, metabolism and excretion. By providing a drug response that is closer to that found in humans, humanised mouse models provide a greater level of confidence in selecting lead compounds for development. These models are applicable in :

• Efficacy and lead selection studies
• Absorption, distribution, metabolism and excretion (ADME) studies
• Drug interaction studies
• Problem solving, and Safety / Toxicity studies

They help to:

• Reduce problems associated with species differences
• Identify compounds tolerated in traditional models but potentially toxic to man
• Identify human-specific metabolites - impossible to generate in traditional models
• Prevent unsuitable compounds from entering the later stages of development
• Reduce the costs of late stage attrition
• Avoid the elimination of potentially successful compounds on the basis of unreliable data
• Address multiple drug metabolism and safety questions at all stages of discovery and development

The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors that recognise, interact with, and are induced by the majority of all known drugs, other xenobiotics and endogenous compounds. The recognition of a drug compound by PXR and / or CAR initiates the activation and co-ordinated expression of a cascade of downstream phase I and phase II metabolic enzymes and phase III drug transporters to eliminate the compound from the body.

PXR and CAR from different species display different ligand-binding specificities. Rodent PXR, for example, can be activated by pregnenolone-16α-carbonitrile (PCN), while the human receptor cannot. In contrast, the human receptor is activated by rifampicin, while rodent PXR is not.

Differences in ligand binding specificity also exist for CAR between human and mouse. For example TCPOBOP ( a potent mouse CAR agonist) and the reverse agonist androstanol are inactive for human CAR.

Species differences in the responsiveness of PXR / CAR to ligands can have a profound effect on downstream metabolic and pathological processes such as:

• Xenobiotic metabolism (Phases I, II and III)
• Acute and Chronic Toxicity
• Infection and Inflammation
• Haem homeostasis
• Liver damage and disease
• Response to chemotherapeutics

The combined use of PXR and CAR knockout, and PXR and CAR humanised models can help to identify which receptors are involved in the human metabolism of a compound, and their relative roles in inducing downstream gene expression.

The PXR/CAR humanised mouse demonstrates specific drug metabolism as metabolised by man and is therefore a more useful model in the testing of drug efficacy and safety than the wild-type mouse.

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