Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of Fragile X-linked mental retardation protein (FMRP), an RNA binding protein that can bind and recognize different RNA structures and regulate the target mRNAs' translation involved in neuronal synaptic plasticity. Perturbations of this gene expression network have been related to abnormal behavioral symptoms such as hyperactivity, and impulsivity. Considering the roles of FMRP in the modulation of mRNA translation, we investigated the differentially expressed genes which might be targeted to revert to normal and ameliorate behavioral symptoms. Gene expression data was analyzed and used the connectivity map (CMap) to understand the changes in gene expression in FXS and predict the effective drug candidates. We analyzed the GSE7329 dataset that had 15 control and 8 FXS patients' lymphoblastoid samples. Among 924 genes, 42 genes were selected as signatures for CMap analysis, and 24 associated drugs were found. Pirenperone was selected as a potential drug candidate for FXS for its possible antipsychotic effect. Treatment of pirenperone increased the expression level of Fmr1 gene. Moreover, pirenperone rescued the behavioral deficits in Fmr1 KO mice including hyperactivity, spatial memory, and impulsivity. These results suggest that pirenperone is a new drug candidate for FXS, which should be verified in future studies.