Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome

Background: Human chromosome 16p11.2 microdeletion is one of the most common copy number variants that confers risk for autism spectrum disorder and other related neurodevelopmental disorders. Animal studies suggest that 16p11.2 deletion may share pathophysiology with Fragile X syndrome (Tian et al., 2015). Data from previous clinical trials suggest that the GABA-B receptor agonist, arbaclofen, may improve symptomatology in some individuals with Fragile X syndrome and idiopathic autism, although the trials themselves did not find statistical significance on their primary endpoints. Taken together, these data raise the intriguing possibility that arbaclofen may be beneficial for 16p11.2 deletion syndrome. Indeed, a recent mouse study supports this possibility (Stoppel et al., 2017). However, the justification for pursuing arbaclofen as a rational therapy for 16p11.2 deletion must be supported by robust preclinical evidence. Concerted efforts to validate early scientific findings may be crucial in addressing the recent paucity of success in translational research (Arrowsmith, 2011).

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.