Improving Translation in Animal Models: The Science, Art, & Anecdotes

Background: Animal models are highly valuable tools for investigating the underlying pathophysiology, genetics, and neurocircuitry of neurodegenerative, neuropsychiatric, neurodevelopmental, and cognitive disorders. Translational endpoints, including behavioral outcomes, are essential for studying these CNS disorders and in particular for Autism Spectrum Disorders (ASD) where diagnostic criteria are largely based on behavioral criteria. Not all behaviors and phenotypes studied in animal models are robust, reliable, or optimal for enabling translational experiments leading to interpretable findings for clinical populations. Indeed, preclinical testing in animal models is critical for drug discovery, and while hundreds of interventions have demonstrated efficacy in animal models, successful translation to the clinic has been limited. Importantly, the preclinical studies that have enabled these clinical trials have largely used male subjects of a single inbred strain which is not analogous to the genetically diverse patient population; nor should it be expected that a single mutation on an inbred strain would recapitulate the diverse spectrum of behavioral phenotypes observed in such complex disorders as ASD. While historically preclinical screening of test compounds have employed behavioral endpoints in animal models as the primary screen owing to a falsely perceived ease of conducting these experiments; there have been compromises on the level of rigor, including blinding, randomization, inclusion of relevant controls, appropriate planned sample sizes, and apriori inclusion and exclusion criteria. Critically, an understanding of a test compound’s pharmacokinetic (PK) and pharmacodynamics (PD) properties is necessary to aid in the selection of relevant and target specific dose ranges, route of administration, and pretreatment regimen for testing, and these PK/PD modeling data are oftentimes not generated. Moreover, having knowledge of a test compound’s therapeutic window, as defined by the dose range that produces the specific pharmacodynamic response relative to the dose range at which adverse or neurotoxic effects occur is crucial to appropriately interpreting the resulting data and its translational utility.

Conclusion: The outcome of implementing these considerations will be discussed in order to improve and enhance the utility of animal models for clinical translation.

Methods: N/A

Results: N/A