Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome
Year: 2023
Type: preprint
Abstract: A microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA-approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine-learning approach to analyze behavior, one lab found that arbaclofen also rescued differences in exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.
Institutions: Simons Foundation, University of Pennsylvania, University of California Davis Medical Center, University of California, Davis, Harvard University, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, National Institutes of Health, Coalition for Aligning Science, University of Iowa
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Simons Foundation, University of Pennsylvania, Simons Foundation Autism Research Initiative, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Centre National de la Recherche Scientifique, PHENOMIN, Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1109023570, G164444715, G1800105685, Par-delà les frontières, l'Université de Strasbourg, G2255650664, G2694206344, Façonner les talents en formation et en recherche à l'Université de Strasbourg, G3047295235, G3310169441, G3357951378, G3815883916, G399734812, G471331628, G4798114250, G6276897512, MIND Institute Intellectual and Developmental Disabilities Research Center, G7002111755, G7240651115, Boston Children's Hospital/HMS Intellectual and Developmental Disabilities Research Center, The Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/Penn, University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (Hawk-IDDRC)
OpenAlex ID: W2970514968