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

Abstract

Abstract Fragile X syndrome (FXS) is one of the neurodevelopmental disorders that is caused by loss of FMRP. Many challenges have not succeeded to develop the proper therapeutics. FMRP is an RNA binding protein which 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 physiological roles of FMRP in the modulation of mRNA translation, we focused to find the differentially expressed genes signature which might be targeted to revert into normal gene expression and amelioration of behavioral symptoms. We analyzed gene expression data and used the connectivity map (CMap) to understand the changes in gene expression signature in FXS and predict the effective drug candidates for FXS. 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 drugs were found to be associated with gene expression changes. Pirenperone, a 5-HT 2A antagonist, was selected and validated as a potential drug candidate for FXS because of its possible antipsychotic effect. Treatment of pirenperone in cultured primary cortical neuron increased the expression level of Fmr1 gene. Moreover, we confirmed the rescue of behavioral phenotypes of FXS using Fmr1 knockout mice with pirenperone treatment. Overall, the results suggest that pirenperone is a new drug candidate for FXS, which should be verified in the future studies.