Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome
Objectives: To rigorously determine the robustness and reproducibility of arbaclofen’s normalizing effects on behavior in 16p11.2 deletion mouse models.
Methods: Four academic labs and one Contract Research Organization are working as a consortium to rigorously assess the behavioral effects of chronic arbaclofen treatment in mouse models of 16p11.2 deletion. Three different mouse models of 16p11.2 deletion on three different background strains and their wildtype controls were treated for at least 12 days with one of three doses of arbaclofen in their drinking water (0.25, 0.5, 1.0 mg/ml). Using harmonized protocols, mice were tested on Open Field activity, Novel Object Recognition, Object Location Memory, Contextual Fear Conditioning and Accelerating Rotarod. Open Field activity was additionally analyzed using 3D imaging and a novel, machine-learning based algorithm that parcellates behavior to sub-second resolution (Wiltschko et al., 2015). Individual performance on these tasks will be correlated with individual home-cage monitoring measures, as well as high-performance liquid chromatography-tandem mass spectroscopy (HPLC-MS/MS) analysis of arbaclofen levels in each brain.
Results: Approximately 180 of the 360 expected animals have been tested behaviorally and for brain penetration levels of arbaclofen. Data collection is ongoing and will be completed in 2018. In the spirit of data transparency, study results will be broadly disseminated regardless of whether they support or refute the initial hypotheses.
Conclusions: Our consortium offers an example of how to develop and execute a rigorous test of preclinical efficacy of a potential pharmacological therapy for a genetic syndrome that predisposes to autism and related disorders.