Validating the cross-species comparative in silico platform (CRISP)

It is widely acknowledged that animal models are not always accurate predictors of the effects of a substance on humans, other animals or the environment. Species of high phylogenetic linkage (mouse-rat or primate-man), do not necessarily possess the same biochemical mechanisms or physiological responses to a particular compound. This lack of predictivity from preclinical species to the clinic is a significant factor in the high attrition rates across a number of bioscience industries and provides significant incentive to develop an in silico platform that can inform researchers as to the most appropriate model system (if any) for investigating the efficacy or toxicity of a given compound.

Moleculomics, a spin out company from Swansea University has created CRISP, a comparative in silico structural/functional platform that offers potential for identifying species differences in liver activity, to help address this problem. CRISP enables users to screen a candidate compound against proteins of the liver to identify predicted molecular interactions (“hits”) and then compare them (in terms of affinity, binding orientation, protein function, and downstream metabolic and signalling pathway effects), to hits in other organisms for the purpose of selecting the most appropriate model for subsequent trials.

Through CRACK IT Solutions, Moleculomics sought industry partners to help validate the technology using in vitro and in vivo hepatotoxicity data. With the support of CRACK IT Solutions funding they have now established a project with Dow Agrosciences to validate CRISP against 10 hepatotoxic compounds and 10 non-toxic compounds (supplied by Dow), the identity of which will be blinded to Moleculomics. Data from the CRISP model will be compared to existing in vitro and in vivo data provided by Dow to evaluate the effectiveness of the model as a cost-effective compound screening method.

The liver is the most commonly affected organ in rodent toxicology studies conducted with (prospective) agrochemical active ingredients. Under current test guidelines, liver toxicity is a key endpoint incorporated in to all in vivo tests in mammalian species. However, the evaluation of agrochemical active ingredients is moving away from a primarily hazard-based evaluation to one based on risk. In a risk-based evaluation, it is only necessary to identify and characterise the ‘critical hazard(s)’. CRISP will help identify critical liver hazards and support the design of an appropriate testing programme, potentially using fewer animals. For example, a two-generation reproductive toxicity study (OECD TG 416) which requires 2000 – 3000 animals (usually rats) is currently required for all agrochemical active ingredients. Using CRISP to identify that liver toxicity is the critical hazard provides evidence to justify not conducting this study. The ability to predict/assess liver toxicity across a broad range of compounds, for example in early stage research projects, will greatly facilitate the selection of suitable candidate(s) and reduce the need to test in vivo to discriminate.

Full details about this CRACK IT Solution and the outputs of the funded project can be found on the CRACK IT website.