Loss of the Sigma-1 receptor disrupts pridopidine-induced gene expression (P4.048)

Objective: Investigate the role of S1R in the mechanism of action of pridopidine. Background: Sigma-1 receptor (S1R) is an ER chaperone protein involved in neuromodulation and neuroplasticity. Pridopidine is a selective S1R agonist small molecule currently in clinical development for Huntington disease by Teva Pharmaceuticals Ltd. Design/Methods: Transcriptomic analysis of WT and S1R-deficient mice treated with increasing concentrations of pridopidine (0, 0.3, 3, 30, or 60 mg/kg) for 10 days. Prefrontal cortex, striatum and hippocampus tissues were collected and profiled via RNAseq. Results: In experiments comparing vehicle-treated WT and S1R KO mice, differential expression analysis revealed significant changes across all brain regions. We identified 26 differential expression genes (DEGs) in prefrontal cortex, 18 in striatum, and 6 in hippocampus (p.adj Conclusions: S1R is necessary for pridopidine-induced gene expression in the CNS. Consistent with previously published data, pridopidine promotes modification of the BDNF and GR pathways in the striatum. Disclosure: Dr. Dreymann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Geva has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Ross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Ross has received research support from Teva Pharmaceuticals Ltd. Dr. Cha has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Cha has received research support from Teva Pharmaceuticals Ltd. Dr. Kusko has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Kusko has received research support from Teva Pharmaceuticals Ltd. Dr. Escalante-Chong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Escalante-Chong has received research support from Teva Pharmaceuticals Ltd. Dr. Zeskind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Laifenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Grossman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Hayden has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries.